40487014 true Safe Administration of Medicines Intervention (SAM-I): a feasibility study of an intervention to de-implement unnecessary double-checking of medicines in hospital SAM-I 1. Are the systems for collecting our primary and secondary outcome measures compatible for use in WP4? 2. Can we improve the efficiency of observational tools for WP4? 3. Is the de-implementation intervention feasible and acceptable to frontline ward staff, and how long does it take? Why/why not? 4. Does the intervention require modifications prior to the main trial to ensure success? If so, what are they and how can they be integrated? 5. Under what conditions does a service become ready to de-implement double-checking (time span, appropriate personnel, infrastructure or policy changes, etc)? Background and study aims Double-checking a medicine before giving it to the patient is often used to reduce medication errors. However, there is no convincing evidence that it works. Nurses spend a lot of time double-checking (6.4 minutes per check), which is estimated to cost the NHS between £412 million and £1.28 billion per year. If double-checking reduces error and patient harm, then this might be time well spent. But evidence shows that double-checking can harm patients by causing delays to them getting critical medicines. This study aims to assess the feasibility, acceptability, and readiness for implementing a co-designed de-implementation intervention that aims to reduce routine double-checking and support safe single-checking of medicines. The study will run over 12 months across three NHS hospital trusts and include six clinical services. Who can participate? Staff members over the age of 18 years employed within a participating ward/service during the study period (e.g., permanent, bank or agency workers) and directly involved in preparing and/or administering medications What does the study involve? The study involves assessing the feasibility and acceptability of implementing a ward-level de-implementation intervention (the SaSI-MEDs Observation Tool) to reduce routine double-checking of medicines and support safe single-checking and to test the study procedures and outcome measures required for a future definitive randomised controlled trial. We will undertake 5-7 observation sessions (lasting about 4-6 hours each) shadowing consenting nurses involved in medication administration, positioning themselves so they can observe practice without obstructing care delivery. The focus of the observation will be on medication administration processes rather than individual staff performance. Observations will take place before and after implementation. All staff involved in medication preparations and/or administrations will also be invited to complete a questionnaire to explore views on single checking and nursing care activities. What are the possible benefits and risks of participating? Although there are no immediate benefits for the nurses participating in the study, it is hoped that the findings of this work will lead to improvements in safely administering medicines in hospitals. If we find that double-checking is no safer than single-checking, it could lead to changes in policy that could reduce double-checking in certain circumstances. This could reduce nursing workload and free up time for staff to carry out more patient-centred tasks and potentially improve the quality of care. We do not expect any disadvantages or risks to being involved. It is important that you understand that we are interested in assessing what is feasible and acceptable to change for safer medication administration. We are not examining your individual knowledge or skills. There is a possibility that you will experience discomfort when being observed. To minimise this, we will try to ensure you are familiar with the research nurse and have had the opportunity to ask questions. Where is the study run from? The study is run from Bradford Teaching Hospitals NHS Foundation Trust and York Trials Unit (University of York) (UK) When is the study starting and how long is it expected to run for? September 2026 to April 2028 Who is funding the study? The National Institute for Health Research (NIHR) Programme Grants for Applied Research (UK) Who is the main contact? 1. Chief Investigator: Professor Beth Fylan, b.fylan@bradford.ac.uk 2. Programme Manager: Dr Lynn McVey, lynn.mcvey@bthft.nhs.uk 3. Senior Research Fellow: Dr Katherine Jones, katherine.jones@bthft.nhs.uk Observed medication administration errors the SAM-I Case Note Review Form pre- (month [M] 0) and post-implementation (M8-10), recording observed errors where a double-check would previously have been mandated by policy. This will be recorded as 'yes' or 'no' per observed medication administration. 1. Nurse attitudes to single-checking measured using the validated Single Checking and Administration of Medications Scale (SCAMS-II) at pre- (M0) and post-implementation (M8-10) 2. Omission of care measured using the care left undone scale at pre- (M0) and post-implementation (M8-10) 3. Double-checking practices measured using the SAM-I Observational Tool at pre- (M0) and post-implementation (M8-10) 4. Service readiness for single checking measured using a checklist and single binary measure at pre-implementation (M0) 5. Length of patient stays measured using routine data collection from electronic Prescribing and Medication Administration systems (ePMA) at post-implementation (M8-10) 6. Reported patient safety incidents (medication-related) measured using routine data collection from Local Risk Management Systems (LRMS) at post-implementation (M8-10) 7. Time spent implementing checks measured using the SAM-I Observational Tool at pre- (M0) and post-implementation (M8-10) 8. Delays in time-critical administrations measured using routine data collection from electronic Prescribing and Medication Administration systems (ePMA) at post-implementation Ethics approval required London - Queen Square Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/LO/0402 10.1186/ISRCTN40487014 367872 CPMS: 74129, NIHR: 206796 367872 74129 206796 Non-randomized study Interventional Non randomised study Treatment 2028-04-01T00:00:00.000Z United Kingdom England RRDN Yorkshire and Humber

St. James's University Hospital Beckett Street

Leeds England LS9 7TF false Ward inclusion criteria: 1. NHS-funded inpatient wards within a participating NHS Trust 2. Wards where medicines administration is frequent and routinely undertaken by nursing staff 3. Wards where double-checking of medicines is embedded within local policy and/or established practice 4. Wards able to support implementation of the intervention, including staff training, policy updates and ward-level engagement activities 5. Wards able to support feasibility data collection, including structured observation of medication administration and access to relevant routine data sources (e.g., ePMA and incident reporting systems) Staff participant inclusion criteria: Staff will be eligible to participate in observation and qualitative evaluation components if they meet the following criteria: 1. Employed (permanent, bank or agency) within a participating ward/service during the study period 2. Directly involved in medicines preparation, administration or supporting the double-checking process (e.g., registered nurses, nurse associates) 3. Aged 18 years or over, consistent with their professional role 4. Willing and able to provide informed consent to participate in observations and other evaluation activities (e.g., questionnaires or interviews where applicable) We will aim to recruit staff representing a range of professional seniority and experience (from newly qualified to senior nurses), diverse ethnic backgrounds, and both substantive ward staff and those working bank or agency shifts to reflect the typical ward workforce. Patients: With CAG approval in place, case note review will be conducted for patients whose medication administration episodes are observed. This will allow comparison between observed practice and prescribed medicines without requiring individual patient consent in order to calculate primary and secondary outcomes. Where paediatric or neonatal wards are included, this may involve review of records for patients under the age of 18 years. Only the minimum necessary patient-identifiable information will be temporarily accessed for linkage purposes, in accordance with CAG approval and data governance procedures. Adult All 1080 0 Patients: Patients will not be directly recruited; however, case note review will not be undertaken where: 1. The medication administration episode was not observed as part of the study 2. The patient (or parent/guardian, where applicable) has exercised their right to opt out of the use of their data for research purposes Only the minimum necessary information will be accessed under CAG approval, in line with approved governance procedures. 2026-09-01T00:00:00.000Z 2028-04-01T00:00:00.000Z Public health Other The intervention is a structured, ward-level approach to reducing routine double-checking and support safe, single-checking for medication administration. It targets ward-level policies and systems, staff motivation, capability and opportunity, norms, and practical workflow processes checking behaviours. Behavioural Data sharing statement to be made available at a later date Protocol

a46d4b4d-ebaa-4fb7-91bc-267ae7694203 2c670fa0-3d8a-4d1c-aa32-f691ee7fee10 d166b709-f3a5-4f13-89a7-4630997e765e 661d1350-4a14-4c34-9521-229a4569186d No Participant information sheet 49920_PIS_V1.2_25Jun2026.pdf 921c416f-9088-4d74-b281-8f483154b41d true application/pdf 289727 1f91b6a3ca743d2d8af6f78784234450 Protocol file 49920_Protocol_V1.2_01Jun2026.pdf c9d29f44-301d-4653-b30e-407636b5daf6 true application/pdf 758551 be8a28e50abd7d33439c10ae52b2fcf7 Beth Fylan https://orcid.org/0000-0003-0599-4537 Principal investigator Scientific

University of Bradford, Richmond Building, Richmond Road

Bradford United Kingdom BD7 1DP +44 (0)1274236952 B.Fylan@bradford.ac.uk Public Lynn McVey https://orcid.org/0000-0003-2009-7682 Public

Bradford Teaching Hospitals NHS Foundation Trust, Bradford Royal Infirmary, Duckworth Lane

Bradford United Kingdom BD9 6RJ - lynn.mcvey@bthft.nhs.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 75400619 true The In Real Life (IRL) Trial: a cluster-randomised controlled trial of a school-based social media reduction intervention versus treatment-as-usual control in secondary school pupils (aged 12–15) in Bradford, UK, and its effects on anxiety (RCADS-25) and secondary outcomes IRL (In Real Life) 1. To estimate the effect of a social media restriction intervention on anxiety (primary outcome) as well as secondary outcomes using a usual-treatment control condition among adolescents in academic years 8, 9, and 10. 2. To explore possible mechanisms underlying the effect of social media restriction. Background and study aims Social media use among children and adolescents has been linked to harms including bullying, sexual risks, and mental health problems. Adolescence is a sensitive period for mental health, with increased risk-taking, ongoing brain development, and the onset of many conditions. Observational studies suggest heavier social media use is associated with more mental health symptoms, but scientific authorities in the UK and US have concluded the average causal effect is unclear. This study is evaluating the effects of an intervention designed to reduce social media media use on mental health among secondary school pupils (academic years 8–10, corresponding to ages 12-15 years). We will explore potential mechanisms underlying these effects. Who can participate? Students enrolled in year 8, 9, or 10 (September 2026), corresponding to ages 12-15 years, at participating secondary schools. What does the study involve? School year groups (academic years 8–10) will be randomly allocated to either (i) a social media restriction app, limiting use to 1 hour per day between 7am and 9pm, or (ii) a treatment-as-usual control condition where the app tracks screen time but applies no restrictions. The intervention will last 6 weeks. Participants will complete a self-reported questionnaire on topics including mental health, bullying, and sleep at baseline (week 0) and follow-up (week 6). Around 30 participants in the intervention group will also take part in qualitative interviews to share their experiences and explore how reducing social media use may affect mental health. What are the possible benefits and risks of participating? Benefits: 1. Possible benefits of the intervention itself (a benefit in terms of mental health). 2. Financial compensation. Risks: 1. Reduced opportunity for social engagement, support, or fear of missing out due to reduced use of social media. 2. Bullying due to participants being left out of social events. 3. Distress experienced during quantitative or qualitative data collection. Where is the study run from? Bradford Teaching Hospitals NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? September 2026 to May 2027 Who is funding the study? 1. The Wellcome Trust (UK) 2. National Institute for Health Research (UK) Who is the main contact? Dr Dan Lewer, borninbradford@bthft.nhs.uk Anxiety the Revised Child Anxiety and Depression Scale (RCADS-25) anxiety subscale self-report survey week 0 (baseline) and week 6 (follow-up) Symptoms of depression the Revised Children's Anxiety and Depression Scale (RCADS) depression subscale self-report survey week 0 (baseline) and week 6 (follow-up) Mental wellbeing the Short Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS) self-report survey week 0 (baseline) and week 6 (follow-up) Ethics approval required East of England - Cambridgeshire and Hertfordshire Research Ethics Committee

2 Redman Place

London United Kingdom EC20 1JQ 26/EE/0127 10.1186/ISRCTN75400619 370130 CPMS: 73987, NIHR: 205448, 337689/Z/25/Z, BTHFT 3191 370130 73987 205448 337689/Z/25/Z BTHFT 3191 Interventional Randomized controlled trial Blinded (masking used) Active Parallel Prevention Not applicable 2027-05-31T00:00:00.000Z United Kingdom England 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 true Updated 29/09/2026: Current key inclusion criteria as of 13/08/2026: 1. Currently enrolled in a secondary school 2. In academic year 8 - 10 3. Can speak and read English Previous key inclusion criteria: 1. Currently enrolled in a secondary school 2. In academic year 8 - 10 3. Owns a smartphone (or regularly uses a specific smartphone that can be used in the research) 4. Can speak and read English Child 12 Years 15 Years All 4500 0 No specific exclusion criteria (all school types and young people will be eligible) 2026-09-07T00:00:00.000Z 2027-03-31T00:00:00.000Z Mental health in healthy young people Mental and Behavioural Disorders Study design: This will be a parallel-arm cluster randomised trial in which school year groups will be randomised to two conditions: (1) an intervention involving a smartphone app designed to reduce social media screen time; (2) a treatment-as-usual control state. The primary outcome will be self-reported anxiety, with other outcomes measured by self-report and the app. We will work with 10-12 secondary schools and randomise 30-36 year groups (academic year groups 8-10 only), with baseline measurements taken when participants join the study and follow-up measurements after six weeks. Intervention arm: The intervention will be a smartphone app for Android and iOS (iPhone), which will limit participants’ use of a pre-defined list of social media and internet browser apps. The app will limit social media through two mechanisms: (i) a daily time ‘budget’ across all linked social media apps and (ii) a ‘curfew’ that prevents linked app use during nighttime hours. Based on coproduction with teenagers, we are planning a daily budget of 1 hour and a curfew from 9 pm to 7 am. We will deliver the intervention over 6 weeks. Control arm: Participants download the same app but receive no active intervention components and the app is only used for passive data collection. Randomisation: School year groups will be randomised in a 1:1 ratio to either the intervention or a treatment-as-usual control condition. Year groups will be randomised within schools, meaning each participating school will have at least one intervention and one control year group. Qualitative research: We will also conduct semi-structured interviews with a purposive sample of ~30 intervention participants during the final week of the intervention and at 6-month follow-up. In these interviews we will explore participants’ experiences and mechanisms by which the intervention may influence mental health outcomes. Behavioural The full dataset will be securely stored at Bradford Teaching Hospitals NHS Foundation Trust, with access restricted to IT staff and named researchers (the Chief Investigator, or another senior member of staff if the Chief Investigator leaves). Personal identifiers will be deleted at the earliest opportunity. An analysis dataset will be available upon request using the Born In Bradford data request process: https://borninbradford.nhs.uk/our-data/how-to-access-data/. Data sharing will be subject to an approved analysis plan and data sharing agreement. Available on request Protocol

69da24f6-75f0-4012-b06f-6ecc5bb8cfd6 bdd0a681-de1b-4d1c-afd9-1366e4aa5578 4490397e-b6bc-4614-a9b9-0bd914b346f6 a6b0ed33-75cd-476e-b964-d4f1f137b8d7 c36b5236-1d73-49a4-95cc-b8638c8d7a22 Yes Protocol file ISRCTN75400619_Protocol_v1.3.pdf ecf93d29-c8bb-4b97-a368-d9382ef48f6f true application/pdf 299182 a78c3ca7a064b840428fa9944952089e Dan Lewer https://orcid.org/0000-0003-3698-7196 Public Scientific Principal investigator

Born in Bradford Office Bradford Institute For Health Research Bradford Royal Infirmary Duckworth Lane

Bradford United Kingdom BD9 6RJ +44 (0)1274 274474 borninbradford@bthft.nhs.uk Public Amy Orben https://orcid.org/0000-0002-2937-4183 Principal investigator

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

Cambridge United Kingdom CB2 7EF +44 (0)1223 355294 info@mrc-cbu.cam.ac.uk Public Bradford Teaching Hospitals NHS Foundation Trust https://ror.org/05gekvn04 Non-commercial Wellcome Trust http://dx.doi.org/10.13039/100010269 National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 79680371 true A feasibility study of the Shared Safety Net Action Plan (SSNAP): a safety-netting intervention that engages patients to support earlier diagnosis of cancer in general practice SSNAP To assess: 1. Whether the delivery of SSNAP is feasible in general practice; 2. Whether SSNAP is acceptable to patients, their families and staff; 3. Whether patient recruitment and follow-up is feasible in general practice; 4a. What outcomes would demonstrate whether SSNAP successfully supports communication and shared decision-making around uncertainty; 4b. What outcomes would demonstrate SSNAP improves patients’ clinical outcomes; 5. How surgeries adapt SSNAP for local use. Background and study aims When doctors aren’t sure what’s causing a patient’s symptoms, they often use a process called “safety-netting.” This means they ask patients to keep an eye on their symptoms and come back if things don’t improve. It’s especially important when symptoms could be an early sign of something serious, like cancer. But sometimes patients forget what they were told or aren’t sure what to look out for. This study is testing a new tool called the Shared Safety Net Action Plan (SSNAP). SSNAP helps patients understand what symptoms to monitor, how long to monitor them, and when to return to the doctor. It also helps GP practices follow up with patients. The aim is to see if SSNAP makes safety-netting clearer and more helpful for patients and staff. Who can participate? Adult patients who visit their GP with vague symptoms that might be linked to cancer—such as tiredness or unexplained weight loss—may be invited to take part. Their family members and GP staff may also be involved. What does the study involve? Patients and families will be asked to fill in questionnaires about their experience of the GP consultation. Some patients who use SSNAP will also be invited to talk to researchers about how it worked for them. GP staff will be interviewed about their experience using SSNAP. The study will also collect data on how often SSNAP is used and what impact it has. What are the possible benefits and risks of participating? Taking part may help patients feel more confident about managing their symptoms and knowing when to seek help. It could also improve communication between patients and their GP. There are no known risks to taking part, and participation is voluntary. Where is the study run from? Bradford Teaching Hospitals NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? March 2025 to April 2028 Who is funding the study? National Institute for Health and Care Research (NIHR). Who is the main contact? Lynn McVey, Lynn.McVey@bthft.nhs.uk Diagnosis of cancer at any stage is measured using anonymised electronic health record data from SystmOne at the end of WP1 (months 5-6 of the study) and in WP3 (months 16-17) 1. Time to re-attend, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 2. Referral(s) for follow-up diagnostic tests, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 3. Number of re-attendances & DNAs over intervention period, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 4. Number of patients re-booking appointments, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 5. Number of occasions intervention used (intervention surgeries) or would be used (control surgeries), anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 6. Willingness of surgeries to be randomised, data collected during interviews and focus groups with participating staff during WP3 (months 16 and 17 of the study) 7. Willingness of staff to initiate SSNAP with patients, data collected during interviews and focus groups with participating staff during WP3 (months 16 and 17 of the study) 8. Number of interviews/ focus groups/questionnaires completed, to be determined when these have taken place, around month 21 9. Intervention patients’/families’ perspectives on SSNAP feasibility & acceptability, collected in patient/carer questionnaires and interviews during WP2 and WP3 (months 8–17 of the study) 10. Consultation satisfaction for intervention & control patients/families, collected in patient/carer questionnaires and interviews during WP2 and WP3 (months 8–17 of the study) 11. Number of eligible patients, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 12. Number of patients followed-up, anonymised data will be collected twice from SystmOne: at the end of WP1 (months 5–6 of the study) and in WP3 (months 16–17) 13. Intervention staff perspectives on SSNAP feasibility & acceptability, including feasibility of data extraction and linkage, data will be collected from staff in interviews and focus groups in WP3 (months 16–21 of the study) Ethics approval required Leeds East REC

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/YH/0163 10.1186/ISRCTN79680371 345898 CPMS: 63265, NIHR: 208819 345898 63265 208819 Interventional cluster randomized Interventional Cluster randomised trial Other 2028-04-30T00:00:00.000Z United Kingdom England Yorkshire and Humber RRDN

St. James's University Hospital Beckett Street

Leeds England LS9 7TF Carer Health professional Patient Patient/carer inclusion criteria for intervention: 1. Patients aged 18 and over presenting with non-specific symptoms which could indicate cancer, who have capacity to decide on their own medical treatment. 2. Patients aged 18 and over presenting with non-specific symptoms which could indicate cancer, who do not have capacity to decide on their own medical treatment, but who are accompanied in the consultation by a family member or informal carer (consultee). 3. Family members or informal carers aged 18 and over who accompany SSNAP-coded patients in consultations. Patient/carer inclusion criteria for questionnaires: 1. Patients aged 18 or over in intervention surgeries who have received SSNAP or who were recorded as eligible to receive SSNAP in control surgeries. 2. Family members/informal carers aged 18 and over who accompany patients in consultations where SSNAP was used in intervention surgeries or where the patient was recorded as eligible to receive SSNAP in control surgeries. Patient/carer inclusion criteria for interviews: 1. Patients aged 18 or over in intervention surgeries who have received SSNAP. 2. Family members/informal carers aged 18 and over whose relative/significant other has received SSNAP in an intervention surgery. Staff inclusion criteria (intervention, interviews, focus groups) 1. All staff in participating surgeries with a safety-netting role (clinical, management/ administrative). Mixed 18 Years 100 Years All 204 0 Patients/carer exclusion criteria for intervention: 1. Young people and children aged under 18 years. 2. Patients aged 18 and over who do not have capacity to consent to their own medical treatment and who either are not accompanied by a family member or informal carer (consultee), or the consultee does not agree to receiving the SSNAP plan. 3. Patients who have opted out of data sharing. Patient/carer exclusion criteria for questionnaires & interviews: 1. Patients who meet the inclusion criterion but for whom participation in questionnaires or interviews could cause distress or confusion, including patients without capacity to consent to the research or patients who are too ill to participate (e.g. at the end of life). 2. Patients, family members/informal carers aged less than 18 years. 3. Family members/informal carers of patients who received SSNAP (in intervention surgeries) or were recorded as eligible to receive SSNAP (in control surgeries) but passed away before the invitation to complete a questionnaire is circulated, so as not to cause unnecessary distress. Staff exclusion criteria: 1. Staff not involved in safety-netting processes. 2026-04-13T00:00:00.000Z 2027-07-31T00:00:00.000Z Cancer Cancer This feasibility study takes the form of a cluster randomised controlled trial. Participants will be adult patients consulting with a primary care practitioner about non-specific symptoms that could be a sign of cancer; adult family members or informal carers who accompany eligible patients in consultations; and staff in participating surgeries with a safety-netting role (clinical, management/administrative). Work package 1 (months 1–6): We will work with six GP surgeries in Bradford, Airedale, Wharfedale and Craven that use the primary care electronic patient record SystmOne and have data sharing agreements in place with Connected Bradford, a whole system data linkage service (<https://bradfordresearch.nhs.uk/connected-bradford/>). Surgeries will be randomised via block randomisation, site initiation visits will take place and surgery staff will be trained (intervention and control training will differ, with intervention surgeries being trained in how to use the SSNAP tool inclusively). SSNAP will be installed on SystmOne in intervention surgeries. In months 5–6, clinicians in participating surgeries will identify through coding in SystmOne adult patients presenting with non-specific symptoms who are eligible for SSNAP. The research team will obtain anonymised data relating to our outcome measures (see A57, A58) for these patients (provided they have not opted out of data sharing) through Connected Bradford to establish a baseline, including anonymised demographic data. As part of a data collection feasibility exercise, staff in two surgeries will also extract the data themselves to test whether this is feasible, but these identifiable data will not be forwarded to researchers. This will inform the feasibility of data collection for a substantive trial for which we will recruit surgeries which do not have data sharing agreements with Connected Bradford. Work package 2 (months 7–15): In intervention surgeries, digital or paper SSNAP will be used as part of routine safety-netting procedures. Using SSNAP, clinicians and patients with non-specific symptoms will agree a plan that specifies which symptoms the patient will monitor, over what time-period, and in what circumstances patients should return. Clinicians will populate the SSNAP template in SystmOne, creating a safety-netting record within patients' electronic notes. Where use of paper SSNAP is more appropriate for patients (see also A33-1), clinicians will also personalise the paper SSNAP form for patients to take away with them. Where digital SSNAP is appropriate, they will generate via SystmOne a personalised letter and a diary for the patient to monitor their symptoms, which will be sent to the patient by text or email. Clinicians can set reminders to contact patients at different priority levels, which appear on the patient home screen whenever a patient record is retrieved, and/or scheduled tasks can be set as reminders, allocating tasks such as contacting patients to specific recipients such as surgery administrators. Clinicians from control surgeries will carry out their usual safety-netting procedures and continue to code patients as eligible for SSNAP in SystmOne. Surgeries will display posters informing patients that the surgery is taking part in research about care of patients who have consulted a clinician with non-specific symptoms and they may be contacted at a future date about this, although they're free not to respond. All patients who have received SSNAP (in intervention surgeries) or who were recorded as eligible for SSNAP (in control surgeries) will be contacted by surgery staff around four weeks after initial consultations. They will be informed that researchers are conducting a study about care of patients who have consulted a clinician with non-specific symptoms where a diagnosis has not yet been reached and invited to complete, with consent, a questionnaire measuring consultation satisfaction (online or post). The questionnaire for people in the intervention arm will ask whether they would be willing to be contacted by the research team about a telephone/online interview (purposively sampled). Researchers will send an information sheet to those patients/carers who indicate an interest in an interview and informed consent will be taken before interviews begin. Patients and carers will be asked in the interviews about SSNAP's feasibility, acceptability, how they used and engaged with it, what they thought about it and how it might best be refined. Questions will be informed by the SSNAP logic model (appended to the protocol). Towards the end of the intervention period, Connected Bradford will provide the same data for patients coded for SSNAP in intervention period as in the baseline period (for patients who have not opted out of data sharing) and anonymised data will be forwarded to researchers. Work package 3 (months 16–30): Researchers will interview staff from each surgery (clinicians, managers, administrators), and will also conduct a staff focus group with staff in each surgery. Interviews and focus groups with staff from control surgeries will assess issues relating to trial design, e.g. willingness of surgeries to be randomised. Those with staff from intervention surgeries will explore SSNAP's feasibility and acceptability, how and why they used it, what factors influenced its adoption and how it might best be refined/further developed. Questions will be informed by the SSNAP logic model (appended to the protocol). Staff involved in delivering SSNAP in intervention surgeries will be asked during interviews and focus groups to complete the System Usability Scale to provide evidence of SSNAP's acceptability. Patient questionnaires and interviews will be completed. Quantitative and qualitative data will be analysed and synthesised (see A62 for methods of analysis). In agreement with our trial steering committee, it will be determined if the intervention should progress to trial and study outputs will be prepared, namely refined paper and digital versions of SSNAP; refined logic model and programme theory; protocol for the substantive trial; and implementation guide with associated training tools. Dissemination will take place through the final trial report; at least two journal articles in international, peer-reviewed open access journals; a conference presentation and through research networks. We will explore routes to wider implementation with our patient and public involvement group, key stakeholders and the steering committee. Behavioural The datasets generated during and/or analysed during the current study will be available upon request from Connected Bradford cbradford@bthft.nhs.uk; type of data are shared linked primary care and secondary care data; data will become available for 10 years or the length of the CB programme; researchers complete a data access application and this is reviewed by the programme manager and considered by Connected Bradford Board; current CB data access process, data are fully anonymised, Connected Bradford REC ref: 22/EM/0127. Qualitative datasets are available on request from Dr Lynn McVey, contact details above. Anonymised data may be shared from interviews and focus groups for qualitative analysis for a maximum of 5 years; participant consent obtained; SSNAP REC ref: 25/YH/0163. Available on request f0851970-a8b2-4c4b-961a-e3c205f5a3b9 62d29a2f-fb3d-48eb-ad00-6574268e112f 69c9b2db-8c32-485e-830b-98ed0cd596f4 Yes Lynn McVey https://orcid.org/0000-0003-2009-7682 Public Scientific Principal investigator

Yorkshire Quality and Safety Research Group, Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Duckworth Lane

Bradford United Kingdom BD9 6RJ - Lynn.McVey@bthft.nhs.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 44597684 true Physical activity for health in South Asian men with prostate cancer: a feasibility study Pro-SAPA The primary research aim is to establish if a physical activity intervention for men of South Asian heritage with prostate cancer is acceptable and feasible for a larger-scale RCT. Background and study aims Prostate cancer is the most common male cancer, with over 50,000 men diagnosed each year in the UK. Studies have shown that different ethnic groups are more or less likely to develop prostate cancer, with South Asian men less likely to develop prostate cancer than white men. This suggests that being South Asian is a protective factor in whether men develop prostate cancer. However, a higher proportion of South Asian men are diagnosed with advanced prostate cancer and die from prostate cancer than non-South Asian men. This research aims to investigate a physical activity intervention of brisk walking in men of South Asian heritage who have been diagnosed with prostate cancer. The main aims of the study are to see whether men are willing to join the study, and whether they stick to doing the physical activity. Overall, the study will help determine if the intervention shows potential promise and if a larger study is worthwhile. Who can participate? Adult men (≥18 years) of South Asian heritage who have previously diagnosed or newly diagnosed with localised or locally advanced prostate cancer. What does the study involve? The study will assess the acceptability of a brisk walking intervention (30 minutes a day, 5 days a week) across two hospitals and the feasibility of conducting a larger clinical trial to investigate whether this intervention improves health outcomes. Men will be asked to participate in a three-month brisk walking intervention and will receive support to motivate them to do so. They will complete questionnaires and logs to record their step count for 1 week when they join the study, and after 6 weeks, 3 months and four months. Information will also be collected from their medical records and through focus groups to find out how they felt about the physical activity. Interviews will also be carried out with some clinicians at the two hospitals to find out how they felt about the physical activity intervention. What are the possible benefits and risks of participating? No benefits and risks provided at registration. Where is the study run from? The University of Bristol, UK. When is the study starting and how long is it expected to run for? July 2025 to January 2027 Who is funding the study? NIHR Bristol Biomedical Research Centre, UK Who is the main contact? Dr Nour Alhusein, nour.alhusein@bristol.ac.uk The feasibility of recruiting men of South Asian heritage with prostate cancer to a physical activity intervention and adherence to the intervention will be measured using questionnaires and logs to record their step counts for 1 week when they join the study, and after 6 weeks, 3 months and four months 1. Implementation fidelity: The extent to which participants complete the brisk walking intervention as prescribed (30 minutes/day, 5 days/week for 3 months). 2. Retention rate: Proportion of participants who remain in the study for the full duration of the intervention. 3. Feasibility of physical activity data collection: Completeness and usability of step count data recorded via pedometers/accelerometers and participant logs at baseline, 6 weeks, 3 months, and 4 months. 4. Feasibility of clinical and self-reported data collection: Completeness of participant-reported outcomes (e.g. symptoms, quality of life) and clinical data (e.g. PSA levels) from questionnaires and medical records. 5. Acceptability of the intervention: Participant and clinician feedback on the walking programme, gathered through focus groups and interviews. 6. Acceptability of trial procedures: Participant feedback on study processes, including reasons for declining participation. 7. Informing future trial design: Use of physical activity and outcome data to guide the development of a larger clinical trial. Ethics approval required West Midlands - Black Country Research Ethics Committee

2 Redman Place

Stratford/London United Kingdom E20 1JQ 25/WM/0113 10.1186/ISRCTN44597684 355170 NIHR: 203315, 2025-858 355170 203315 2025-858 Multicentre single-arm open-label feasibility trial Interventional Non randomised study Prevention 2027-01-31T00:00:00.000Z United Kingdom England Bradford Teaching Hospitals NHS Foundation Trust

Bradford Royal Infirmary Duckworth Lane Bradford BD9 6RJ

Bradford England BD9 6RJ North Bristol NHS Trust

Southmead Hospital, Southmead Rd, Bristol BS10 5NB

Bristol England BS10 5NB Health professional Patient Participants may enter the study if ALL of the following apply: 1. Adult men (≥18 years) 2. Previously diagnosed or newly diagnosed with localised or locally advanced prostate cancer 3. South Asian heritage 4. Capacity to give informed consent Mixed 18 Years 100 Years Male 30 0 Participants may not enter the study if ANY of the following apply: 1. Inability to give informed consent 2. Identified as unsuitable to participate by their clinician, e.g. due to co-morbidities, treatment being received, or any other contraindications to exercise 3. Use of a mobility aid other than a walking stick, which would prevent them from carrying out the brisk walking intervention 4. Inability to give informed consent 2025-10-08T00:00:00.000Z 2026-10-02T00:00:00.000Z Physical activity in South Asian men with prostate cancer Cancer This research aims to investigate a physical activity intervention of brisk walking in men of South Asian heritage who have been diagnosed with prostate cancer. The study will look at the acceptability of the brisk walking intervention (30 minutes a day, on 5 days a week) across two hospitals, and the feasibility of later conducting a larger clinical trial to look at whether the brisk walking intervention improves health. Men will be asked to complete the brisk walking intervention for three months and will receive support to motivate them to do so. They will complete questionnaires and logs to record their step count for 1 week when they join the study, and after 6 weeks, 3 months and four months. Information will also be collected from their medical records and through focus groups to find out how they felt about the physical activity. Interviews will also be carried out with some clinicians at the two hospitals to find out how they felt about the physical activity intervention. The main aims of the study are to see whether men are willing to join the study, and whether they stick to doing the physical activity. Overall, the study will help determine if the intervention shows potential promise and if a larger study is worthwhile. Behavioural The datasets generated during and/or analysed during the current study will be stored in the University of Bristol Research Data Repository with restricted access data.bris (https://data.bris.ac.uk/data/) Stored in publicly available repository Protocol

Study website Migrated from study website field

93a012e2-0ef3-4713-a65a-e251ce3c83bb 0c18d4cc-78f5-4cb8-bad8-4f0229b98bb8 a8f14632-75c1-4bd1-936b-ebc5341494a5 72bb09d4-0c8e-4f07-bbfd-43217cc9e7bc Yes Protocol file ISRCTN44597684 Pro-SAPA Study protocol V4 22.04.26.pdf 9a0780ee-6a52-4a98-addf-d419a0dfd7eb true application/pdf 893532 ad9ed232c8fd54972db2073a6d986eb4 Athene Lane https://orcid.org/0000-0002-7578-4925 Public Scientific Principal investigator

University of Bristol 1-5 Whiteladies Rd

Bristol United Kingdom BS8 1NU +44 (0)1174552266 Athene.Lane@bristol.ac.uk Public Nour Al Husein https://orcid.org/0000-0001-7986-743X Public Scientific

University Of Bristol Canynge Hall

Bristol United Kingdom BS8 2PS +44 (0)1174559673 nour.alhusein@bristol.ac.uk Public University of Bristol University/education https://ror.org/0524sp257 Non-commercial NIHR Bristol Biomedical Research Centre http://dx.doi.org/10.13039/100015250 84780524 true A quasi-experimental evaluation of the effectiveness of a community-based breastfeeding support intervention in promoting breastfeeding rates at 6-8 weeks postpartum in the Better Start Bradford cohort. Primary Hypothesis Participation in the BFS intervention will increase the likelihood of any form of breastfeeding at 6–8 weeks postpartum compared to standard care in the Better Start Bradford (BSB) cohort. Secondary Hypotheses Exclusive Breastfeeding: Participation in the BFS intervention will increase the likelihood of exclusive breastfeeding at 6–8 weeks postpartum compared to standard care. Any Breastfeeding: Mothers who receive the BFS intervention will have higher rates of any breastfeeding at 6 months postpartum compared to those receiving standard care. Pre- vs. post-pandemic comparison: The rate of exclusive breastfeeding at 6-8 weeks postpartum will be higher among mothers who received in-person BFS support pre-pandemic, compared to those who received virtual/telephone BFS support during the pandemic. Intervention Dose: A higher number of support contacts (intervention dose) will be associated with a greater likelihood of any and exclusive breastfeeding at 6–8 weeks postpartum. Delivery Format: Breastfeeding rates at 6-8 weeks postpartum will be higher among mothers who received in-person BFS support compared to those who received telephone support (independent of pandemic) Interpreter Use: Mothers who require an interpreter will have lower breastfeeding rates at 6–8 weeks postpartum compared to those who did not. Participant Characteristics: Mothers with English as a second language will have lower breastfeeding rates at 6–8 weeks to native English speakers. Background and study aims This study will explore whether a community-based programme to provide breastfeeding Support to new mothers in the Better Start Bradford area helps them to continue breastfeeding their babies 6 to 8 weeks after birth, compared to not if they did not get the support. Research shows that breastfeeding has many benefits for both mothers and babies, but the UK has some of the lowest rates of breastfeeding in the world. Many women stop breastfeeding earlier than they would like to, often due to a lack of timely support. The Breastfeeding Support programme was established to address this by offering direct and emotional support to new mothers through trained breastfeeding support workers. The service was also adaptable, with face-to-face, phone calls, or video calls. During the COVID-19 pandemic, however, support was entirely phone and video contact. The main question is whether women who received support through the programme were more likely to be still breastfeeding at 6–8 weeks compared to similar women who did not receive the intervention. It also explores whether the programme helped with exclusive breastfeeding (where babies receive only breast milk), whether its impact lasted until six months, and whether changes in how the service was delivered during the pandemic affected its success. The study will also check if results are different based on the format of the support (in-person or remote), the spoken primary language of the woman, or their need for an interpreter. Who can participate? Mothers (>18 years) who participated in the Breastfeeding Support intervention with at least one support contact, completed the BSB BiBBS baseline questionnaire (the consent and baseline data cohort), and neither mother nor baby was admitted to the ICU/NICU after delivery. What does the study involve? For this, researchers are using existing data from a large local project called Born in Bradford’s Better Start (BiBBS), which has tracked the health and experiences of thousands of mothers and babies over approximately 10 years. Some mothers in BiBBs received the Breastfeeding Support intervention, and some did not. By using a method called propensity score matching, the researchers will compare women who are similar in key characteristics, such as age, ethnicity, breastfeeding intentions, and depression. Data to support this study comes from three main sources: a questionnaire completed by mothers during pregnancy, service records from the Breastfeeding Support programme, and health visitor records documenting how babies were fed at 6–8 weeks and 6 months. In addition to analysing whether the programme helps to promote breastfeeding, the team will consider the cost of delivering the programme. They will compare those costs with the known long-term health benefits of breastfeeding to estimate whether the programme offers good value for money. The evaluation does not involve new data collection; it uses data already gathered through routine care and the BiBBS cohort. Ethical approval for this kind of research was granted when the BiBBS study began, and strict data privacy procedures are followed. The results of the study will be shared through scientific publications, community newsletters, social media, and other public channels. The goal is to provide useful insights for healthcare providers, local services, and decision-makers about whether this kind of community support program should be continued or expanded. What are the possible benefits and risks of participating? There are no anticipated additional risks or benefits, as all processes are part of standard midwifery care, and all data collection has been undertaken as part of the existing BiB/BiBBS studies. Any potential risks from participants completing mental health measures are mitigated through those collecting the measures being trained in Good Clinical Practice, and by providing opportunities for signposting to relevant services. Where is the study run from? Better Start Bradford, Better Start Bradford Innovation Hub (UK) When is the study starting and how long is it expected to run for? November 2015 to March 2024 Who is funding the study? The National Lottery Community Fund (UK) Who is the main contact? Behnam Tajik, behnam.tajik@york.ac.uk Any breastfeeding at 6–8 weeks postpartum is measured using linked routine data collected from health visitor records (SystmOne) at one time point (the mandated 6-to-8-week review). This is recorded as a binary measure (any breastfeeding = 1 / no breastfeeding = 0). 1. Exclusive breastfeeding at 6–8 weeks postpartum is measured using linked routine data collected from health visitor records (SystmOne) at one time point (the mandated 6-to-8-week review). Binary measure: exclusive breastfeeding = 1 / not exclusive = 0. 2. Any breastfeeding at 6 months postpartum is measured using linked routine data collected from health visitor records (SystmOne) at one time point (6-month health-visitor contact). Binary measure: any breastfeeding = 1 / no breastfeeding = 0. Subgroup / secondary analyses: 1. Impact of intervention delivery mode: compare outcomes by delivery mode (face-to-face vs telephone/virtual). Analysis: stratified and interaction analysis within logistic regression models (treatment × mode). 2. Dose–response (number of support contacts): correlation between number of BFS contacts and breastfeeding outcomes; modelled as both continuous and categorised (e.g., above/below median) covariate; trend tests and marginal effects reported. 3. Interpreter use: compare outcomes for participants where an interpreter was used vs not used; adjusted logistic regression and subgroup checks. 4. English language proficiency: subgroup difference (English first language vs English second language); adjusted models and interaction tests. 5. Pre- vs post-pandemic implementation effects: compare outcomes for participants who received the intervention pre-COVID (in-person) vs during COVID (telephone/virtual), including an assessment of the implementation period as an effect modifier. 6. Cost-effectiveness / economic threshold analysis: planned cost analysis of programme delivery costs plus a threshold analysis linking plausible long-term health benefits to cost-effectiveness (NICE Reference Case framework used where possible). This will be described at a high level in the registry; detailed methods will be in the analysis plan. Ethics approval required Yorkshire & The Humber - Bradford Leeds Research Ethics Committee

Room 001, Jarrow Business Centre, Viking Industrial Park Rolling Mill Road

Jarrow United Kingdom NE32 3DT 15/YH/0455 10.1186/ISRCTN84780524 188581 CPMS: 30638 188581 30638 Quasi-experimental evaluation using propensity score matching to compare intervention participants with matched controls Interventional Non randomised study Efficacy 2024-03-31T00:00:00.000Z United Kingdom England Better Start Bradford

Bradford United Kingdom BD5 9NP Service user 1. Mothers who participated in the Breastfeeding Support intervention with at least one support contact 2. Completed BSB BiBBS baseline questionnaire (the consent and baseline data cohort) 3. Neither mother nor baby was admitted to the ICU/NICU after delivery Adult 18 Years Female 1186 1770 1. Mothers who did not complete the BSB and BiBBS baseline questionnaire 2. Mothers or babies admitted to the ICU/NICU post-delivery 2018-10-01T00:00:00.000Z 2024-03-31T00:00:00.000Z Maternal and child health, specifically focusing on: Breastfeeding support Breastfeeding rates at 6–8 weeks and 6 months postpartum Pregnancy and Childbirth This is a quasi-experimental evaluation using propensity score matching to compare intervention participants with matched controls within the Born in Bradford Better Start cohort. Participants in the Breastfeeding Support (BFS) Programme are typically enrolled shortly after birth, with the first support contact ideally occurring within the first few days postpartum. The BFS Programme is a community-based behavioural intervention designed to promote and sustain breastfeeding among new mothers. It is particularly relevant in communities with lower breastfeeding rates and among groups who may face social, cultural, or language-related barriers to sustained breastfeeding. The programme is delivered by trained Breastfeeding Support Workers (BSWs), who provide both practical and emotional support tailored to each mother’s needs. Support is offered in a flexible format, including face-to-face home visits, community-based sessions, and telephone or video calls. Each mother receives at least one contact with a BSW, and the number of subsequent contacts varies depending on individual needs. The support includes guidance on breastfeeding techniques, managing common breastfeeding challenges, and encouragement to help mothers meet their breastfeeding goals. In the Better Start Bradford (BSB) area, the BFS Programme was adapted in response to the COVID-19 pandemic in March 2020. All support transitioned to telephone or video delivery during the pandemic period, before gradually returning to a mixed model that included face-to-face support. Study outcomes are drawn from routine data collected through the Born in Bradford’s Better Start (BiBBS) cohort. These include questionnaire data collected during pregnancy, BFS service records documenting support contacts, and health visitor records on infant feeding status at 6–8 weeks and 6 months postpartum. As all data are derived from routine sources, no additional data collection is required for the evaluation. If a participant has relevant data recorded in more than one source, the BiBBS dataset will be prioritised. Behavioural Researchers are encouraged to make use of the BiB data, which are available through a system of managed open access. Before contacting the researchers, please read the Guidance for Collaborators (https://borninbradford.nhs.uk/research/guidance-for-collaborators/). The BiB executive reviews proposals monthly and will endeavour to respond to requests as soon as possible. Find out about the different datasets in the Data Dictionary (https://borninbradford.github.io/datadict/) or contact a member of the BiB team (borninbradford@bthft.nhs.uk). Once you have formulated your request, please complete the ‘Expression of Interest’ form available here (https://borninbradford.nhs.uk/wp-content/uploads/BiB_EoI_v3.1_10.05.21.doc) and send it to borninbradford@bthft.nhs.uk. If the request is approved, you will be asked to sign a Data Sharing Contract (https://borninbradford.nhs.uk/wp-content/uploads/BIHR-Data-Sharing-Contract.docx) and a Data Sharing Agreement (https://borninbradford.nhs.uk/wp-content/uploads/BIHR-Data-Sharing-Agreement.docx), and if the request involves biological samples, you will need to complete a material transfer agreement (https://borninbradford.nhs.uk/wp-content/uploads/BiB-Material-Transfer-Agreement-v4-0.docx). Born in Bradford (BiB) is a longitudinal research project. BiB aims to work out why some people have good health or well-being, while others have difficulties. To do this, BiB collects information from participants about all aspects of their lives at different ages using surveys, research clinics and other assessments. BiB also gathers information about families from other sources, such as health records or environmental records. BiB processes the data to make sure it is accurate, well organised, and to make it so that no person can be identified from the data. BiB then shares this processed data with scientists conducting research with potential public benefit. These scientists can be based anywhere in the world. The data that is available to be shared can be seen here: https://borninbradford.github.io/datadict/bibbs/. Available on request Protocol

Statistical Analysis Plan (SAP) & Open Science Framework (OSP)

Study website Migrated from study website field

8790ee74-ebaf-41c1-a358-d7016227fdb5 3ee988e2-c212-4251-bddc-1243b9ce4bc2 cfac48d3-5a15-4d8e-a7e9-4b463efcb80a 2aa4e589-e935-4f0f-9a44-8725f4a81d6c Yes Protocol file 47800_Protocol_V1.0_23July2025.pdf ba043ace-cfe8-4f49-82a7-a04e1ac3b351 true application/pdf 618648 b97b348a700b0587f2a8c75a78bbdc1f Statistical Analysis Plan (SAP) & Open Science Framework (OSP) 47800_SAP.pdf e7447799-86ea-4ac2-9b4a-7b1366208835 true application/pdf 196555 3027178dc5dabfa2432389802da8a949 Maria Bryant https://orcid.org/0000-0001-7690-4098 Public Principal investigator

University of York Heslington

York United Kingdom YO10 5DD +44 (0)1904 321321 maria.bryant@york.ac.uk Public Behnam Tajik https://orcid.org/0000-0002-8453-3909 Scientific

University of York Heslington

York United Kingdom YO10 5DD +44 (0)1904 321321 behnam.tajik@york.ac.uk Public Bradford Teaching Hospitals NHS Foundation Trust Hospital/treatment centre https://ror.org/05gekvn04 Non-commercial National Lottery Community Fund http://dx.doi.org/10.13039/501100013529 32222362 true Evaluating the indoor environment, health, carbon emission, economic outcomes of retrofitting social housing properties to improve energy efficiency in a low-income multi-ethnic population: a quasi-experimental study with process evaluation Healthy Homes We aim to assess the impact of improving the energy efficiency of social housing ('retrofit') on indoor environmental quality (including temperature, relative humidity, damp/mould, and indoor air quality (e.g. NO2, PM2.5, carbon dioxide [CO2]), health, and environmental and economic impacts. We will explore trade-offs in indoor conditions and other potential unexpected consequences, along with contextual and system factors which affect implementation and resident experience. Our research questions (RQ) are: RQ1: What is the impact of retrofit up to 12 months post-retrofit on: A) temperature, B) thermal comfort, C) indoor air quality (focusing on NO2, PM2.5, and air change rates) D) risk of damp/mould; E) energy use, F) self-reported satisfaction and mental and respiratory health? RQ2: A) What is the impact of retrofit up to 5 years post-retrofit on adult residents’ acute health care use related to i) mental health, ii) respiratory health, and iii) cardiovascular health?; B) Are there differential impacts for vulnerable groups (those with pre-existing health issues)? RQ3: What is the impact of retrofit on short- and long-term A) exposure to indoor environmental conditions and carbon emissions (3A), and B) health and economic impacts? (3B) RQ4: A) How was the retrofit implemented, and what system, and wider contextual factors influenced the implementation? B) Was the implementation as intended (from the perspective of residents and other stakeholders) and are there any unexpected consequences from implementation? Background and study aims The quality of our homes can have a big impact on our health. Cold, damp, or poorly ventilated homes can lead to problems like mould, indoor air pollution, and stress, which may increase the risk of heart and lung conditions. Making homes more energy-efficient—known as retrofitting—can help improve health, reduce energy bills, and lower carbon emissions. However, if not done carefully, retrofitting could also reduce fresh air and make damp or pollution worse. This study is working with a large social housing provider in Bradford to find out how retrofitting affects people’s health, indoor air quality, and whether it offers good value for money. The results will help guide future housing improvements to benefit both people and the environment. Who can participate? Residents living in selected social housing properties in Bradford may be invited to take part. Some homes will be retrofitted, and others will be used for comparison. What does the study involve? If you take part, we may install small sensors in your home to measure air quality, temperature, and humidity. You’ll be asked to complete short surveys about your health, comfort, and energy use at three different times. In some homes, we’ll also measure mould and how windows are used for ventilation. A small number of residents will be invited to take part in interviews to share their experiences. What are the possible benefits and risks of participating? Taking part could help improve understanding of how to make homes healthier and more comfortable. It may also help shape future housing policies. There are no major risks, but some people may find the surveys or sensors slightly inconvenient. All information will be kept private and secure. Where is the study run from? Bradford Teaching Hospitals NHS Foundation Trust in partnership with a major social housing provider (UK) When is the study starting and how long is it expected to run for? July 2025 to December 2029 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Dagmar.Waiblinger@bthft.nhs.uk Temperature measured via the AirGradient sensor in 5-minute periods continuously from baseline until monitoring ends in Spring 2027 1. Indoor air quality (PM2.5, CO2, NO2, relative humidity) measured via the AirGradient sensor in 5-minute periods continuously from baseline until monitoring ends in Spring 2027 2. Energy use measured via energy meter readings at four time periods: the start and end of winter 2025/2026 and start and end of winter 2026/2027 3. Mould concentrations measured via a mould sensor in winter 2025/2026 and winter 2026/2027 (in a subset of homes) 4. Resident thermal comfort and satisfaction measured via questionnaire in winter 2025/2026 and in winter 2026/2027 5. Resident self-reported respiratory and mental health via questionnaire in winter 2025/2026 and in winter 2026/2027 Ethics approval required Yorkshire & The Humber - Bradford Leeds Research Ethics Committee

NHSBT Newcastle Blood Donor Centre, Holland Drive

Newcastle-upon-Tyne United Kingdom NE2 4NQ 25/YH/0081 10.1186/ISRCTN32222362 347237 CPMS: 64093, NIHR: 165582 347237 64093 165582 Observational cohort study Observational Cohort study Quality of life 2029-12-31T00:00:00.000Z United Kingdom England 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 Patient WP1 1. Homes managed by Incommunities, with energy performance certificate EPC) rating less than ‘C’ and identified for retrofitting 2. Eligible homes will have retrofitting scheduled from March to October 2026 (intervention) Or after March 2027 (Control group). Ideally the control homes are a close match to the intervention homes in building age, type, and EPC 3. Residents of eligible home able to give informed consent and are 18 years or over WP4 Interviews with resident 1. Participants who consented to WP1 and whose household is part of the intervention group 2. After a participant of such a household consented, other residents with minimum age 18 years of the same household will become also eligible , if they are able to give informed consent Non-resident Stakeholder interviews 1. Participants over the minimum aged of 18 years and have consented to be interviewed 2. Participants involved in social housing and delivering good indoor air quality Peer Researchers 1. Participants over the age of 18 years and consented to be part of study 2. Participants who belong to the same community where the research is taking place 3. Able to speak English well (additional languages welcomed) Mixed 18 Years 99 Years All 430 0 WP1 1. Households which are not scheduled for retrofitting according to the required timeline 2. Language barrier that can not be overcome with support of bilingual research assistants 3. Lack capacity for informed consent WP4 Resident Interviews 1. Households which are not scheduled for retrofitting according to the required timeline 2. Lack capacity for informed consent 3. Language barrier that can not be overcome with support of bilingual research assistants Non-resident stakeholder interviews 1. Not involved in social housing or air quality 2. Lack capacity for informed consent 3. Language barrier that can not be overcome with support of bilingual research assistants Peer researchers 1. Lack capacity for informed consent 2. Unable to speak English well 2025-07-15T00:00:00.000Z 2026-01-31T00:00:00.000Z Public Health, Persons with potential health hazards related to socioeconomic and psychosocial circumstances Other The Healthy Homes project is structured into four work packages (WPs) with both quantitative (WP1, WP2, WP3A + 3B) and qualitative (WP4) methods. WP1 and WP4 will require engagement with the public, recruitment/taking consent and data collection whilst WP2 will carry out secondary data analysis on the Connected Bradford dataset. WP3A utilises data collected as part of WP1 in order to model the changes in indoor conditions and energy/carbon exposures for a range of housing archetypes. WP3B is a health economic evaluation which utilises findings from WP3A to model the longer-term economic, productivity, and health impacts. Therefore, the methodology in the following will focus on WP1 and WP4. WP1: Residents of homes of interest will be made aware that they are eligible to take part in the study, information will be sent through Incommunities or directly to the household and raising awareness and engagement within the community. Potential participants will be able to express their interest through various channels: either by phone, email, online, post, face to face and will provide their contact details. Potential participants that have previously consented to be part of one of our Born in Bradford cohorts and are identified as living at an eligible address, can be contacted directly (phone or letter) as they have consented to contact for further studies. The Healthy Home team will contact interested residents and discuss their participation and ensure that they have access to the participant information sheet. A home visit will be arranged with residents who would like to take part at a convenient date and time. At the first study visit: The fieldworker will complete the consent form with the resident in the household that will complete the baseline questionnaire (Survey 1) and subsequent questionnaires. The baseline questionnaire will be completed as part of the visit. An air pollution sensor (AirGradient) will be installed in the main living area ensuring that the sensor's own internet connection is working. Ideally, monitoring will continue until the sensor is picked up 18 to 21 months later in March 2027 (from set up in the 3rd quarter of 2025). Participants will receive monthly vouchers (£20) each month of the monitoring period. The participant will receive a contact schedule considering his/her contact preferences. Subsequent questionnaires: Participants will receive three additional questionnaires to complete, roughly each about 6 months apart, covering the Winter 2025/26 (Survey 2), Summer 2026 (Survey 3) and Winter 2026/2027 (Survey 4) periods. Questionnaires will be deployed according to participant preferences as an online link via email, in paper form, over the phone or as part of a home visit. Energy meter readings: We will collect energy meter readings before and after each winter period (e.g. 4 measurements in total). As much as possible we will tie these readings in with existing scheduled contacts. We give participants the option to take the reading themselves or to be taken by the fieldworker. Additional measurements (sub-sample): Mould sensor measurement: we may ask a smaller number of participants at the first visit whether they would agree to mould measurements at different time points. We will confirm with the participant each time that they are still happy with a repeat measurement. Measuring ventilation: we may ask participants whether they would be happy to accommodate window sensors on the windows in the living room for periods of time, for example in the winter. We will provide further information before any deployment and confirm that the participant is happy to have these installed. We aim for that visits for installation or de-installation to coincide with scheduled contacts, for example, subsequent questionnaires, mould sensor measurements and/or delivery of voucher. WP4: Interviews Participants of the intervention group will be asked at the first visit whether they would be happy to receive information about interviews carried out as part of WP4. Interested participants will receive further participant information in the winter period following recruitment. Up to 20 participants will become part of this sample and will sign a separate consent form prior to the interview. The interview will be conducted by a researcher using an interview guide and will take place at the participants home, or online, according to participant preferences. A further interview will take place one year later after the retrofitting has taken place. Participants will receive a £20 voucher for each interview. 10 non-resident stakeholders will also be interviewed. These will be those involved in social housing and delivering good indoor air quality and will be recruited through key contacts and snowball sampling. They will sign a separate consent form. The interviews will be conducted by a researcher of the Healthy Homes team using a different interview guide at a community venue, or online. These interviews will take place at two points, these are planned for Summer 2026 and Spring 2028. WP4-Peer Research 10 Peer-researchers will be recruited by one or two community organisations. If they wish to be part of the study, they will sign a consent form. They will then undertake some training and work with the research team to design a study (this in unknown at present but could include photographs, questionnaires, mapping, audio recordings, workshops). Each peer researcher will collect data from 10 residents, in phase 1 and 10 residents in phase 2 (12-18 months later). We will provide the ethics committee with further details of these activities as part of an amendment, prior to this element of the work starting. Other Quantitative data collected in this study will be available as part of the Born in Bradford repository. Data will be cleaned prior to availability. All data collected have been granted ethical approval and participant consent for its continued availability. Data requests are made to the BiB executive using the form available from the study website: http://www.borninbradford.nhs.uk (please click on ‘Our Data’ and ‘How to Access Data’ to access the form and guidance). All requests are carefully considered and accepted where possible. Available on request Stored in publicly available repository

Study website Migrated from study website field

6e32c2bd-c636-4ee9-8548-dca3df3e20d5 63628c2a-3cf6-4af0-902c-9566949ee5f4 95db7c97-a598-4913-a25e-ce5e302cd931 46e9a8bd-8da3-402f-82ac-e727237af2e3 95acc0cd-42e8-4bc9-8957-9e61287c96e5 Yes Participant information sheet 47626 2-WP1-Healthy-Homes-PIS_-V2.0_12052025.pdf e0ab1229-5bc3-402d-b9aa-1ae96d9cfa70 true application/pdf 150326 62955e3bad6f622f7408bf3506be1a05 Dagmar Waiblinger Public Scientific Principal investigator

Bradford Institute for Health Research, Bradford Royal Infirmary Temple Bank House, Duckworth Lane

Bradford United Kingdom BD9 6RJ +44 1274383317 Dagmar.Waiblinger@bthft.nhs.uk Public Tiffany Yang https://orcid.org/0000-0003-4549-7850 Public Scientific Principal investigator

Bradford Institute for Health Bradford Royal Infirmary

Bradford United Kingdom BD9 6RJ - Tiffany.Yang@bthft.nhs.uk Public Ella Foggitt Public

Bradford Institute for Health Bradford Royal Infirmary

Bradford United Kingdom BD9 6RJ - Ella.Foggitt@bthft.nhs.uk Public Bradford Teaching Hospitals NHS Foundation Trust Hospital/treatment centre https://ror.org/05gekvn04 Non-commercial NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) 63771613 true Evaluating the impact of the EpiSafe bundle on care and clinical outcomes for pregnant women with epilepsy and their babies: a cluster randomised hybrid implementation-effectiveness trial, process evaluation and qualitative study with economic evaluation EpiSafe The implementation of the EpiSafe bundle at antenatal booking will increase the proportion of high-risk pregnant women with epilepsy accessing specialist epilepsy care before 14 weeks’ gestation and improve maternal and perinatal outcomes. Background and study aims Every year in the UK, around 2,500 women with epilepsy get pregnant. Epilepsy is one of the leading causes of maternal death and women with epilepsy face higher risks during pregnancy such as miscarriage, high blood pressure, early birth, and problems with the baby’s growth. During pregnancy, changes in the body can affect seizure patterns and how medicines which help control epilepsy are processed in the body. Some women stop taking their medication on their own because they worry it may harm their baby. These factors can increase the risk of seizures which is why specialist epilepsy care is recommended during pregnancy. However, in practice, many don’t receive specialist care or early enough. For this study, a new programme (the EpiSafe bundle) has been developed, which aims to support more women accessing specialist care during pregnancy and to improve overall health outcomes. Who can participate? The study will take place at NHS Maternity Units across the UK. The study design (cluster randomised controlled trial) means that all pregnant women aged 18 years and over with epilepsy who attend the antenatal clinics at participating maternity units will automatically be part of the study if they meet the study inclusion criteria. While pregnant women with epilepsy will not be approached to consent to take part in the study, they will be made aware of its existence and the use of their data through a study poster and dedicated website. Women will have the option to opt out of data collection via the national NHS digital data opt-out system. What does the study involve? Midwives in the maternity units randomly allocated to the ‘EpiSafe bundle’ will apply the ‘EpiSafe bundle’ at the first antenatal appointment. It includes a short risk assessment to identify pregnant women with epilepsy at increased risk and refer them early to an epilepsy specialist. If a maternity unit is allocated to EpiSafe, all eligible women with epilepsy attending that unit will automatically receive the EpiSafe intervention as part of their standard care during their antenatal booking visit. In the units allocated to usual care (the control group), women will be booked according to the standard guidelines according to the National Institute for Health and Care Excellence (NICE) and the Royal College of Obstetricians and Gynaecologists guidelines. The study will also involve interviews with two different groups: 25 – 30 healthcare professionals and 18 – 24 women with epilepsy at maternity sites allocated to the EpiSafe bundle. These interviews will explore what poses barriers to and what helps health professionals use the EpiSafe bundle and pregnant women’s experiences of being exposed to it. What are the possible benefits and risks of participating? The EpiSafe bundle has the potential to increase access to specialist epilepsy care in the first 14 weeks for women at high risk due to their epilepsy. The study primarily uses data collected as part of routine care and therefore minimises disruption to the lifestyle and care of women with epilepsy. There are no anticipated risks to pregnant women with epilepsy cared for in the maternity units in the intervention arm. This is because their care and their care pathways remain the same. The intervention will only aid in the systematic assessment of the high-risk women and early referral to specialist epilepsy teams. Where is the study run from? The project is being sponsored by the University of Liverpool and is being conducted in collaboration with Anglia Ruskin University and Birmingham City University (UK) When is the study starting and how long is it expected to run for? April 2015 to February 2028 Who is funding the study? National Institute for Health and Care Research (UK) Who is the main contact? John Allotey, john.allotey@liverpool.ac.uk Proportion of high-risk pregnant women with epilepsy accessing specialist epilepsy care in first 14 weeks of gestation, calculated as a percentage of all those considered to be at high risk ; Timepoint(s): At 14 weeks of gestation Current key secondary outcome(s) as of 23/02/2026: 1. The occurrence of any type of seizure, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 2. Increase in the frequency or severity of seizures, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 3. Prolonged epileptic seizures lasting 30 minutes or a series of seizures with incomplete return of consciousness (status epilepticus), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 4. Death of pregnant women, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy or within 42 days of termination of pregnancy 5. Occurrence of epileptic seizures that result in altered consciousness, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 6. Accidents or injuries directly resulting from seizure activities, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 7. Any hospital admissions resulting from seizure activity during pregnancy, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 8. Admission to high dependency or intensive care unit for any reason, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 9. Anti-seizure medication adherence during pregnancy, obtained from care provider log; Timepoint(s): During pregnancy 10. Development of new-onset hypertension and proteinuria after 20 weeks of gestation (pre-eclampsia), obtained directly from patient records and clinical notes; Timepoint(s): After 20 weeks of gestation 11. Onset of labour before 37 weeks of gestation, obtained directly from patient records and clinical notes; Timepoint(s): At 37 weeks of pregnancy 12. Rupture of membranes before the onset of labour, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 13. Premature separation of the placenta from the uterine wall (placental abruption), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 14. Blood loss of 500 ml or more from the genital tract within 24 hours of birth (postpartum haemorrhage), obtained directly from patient records and clinical notes; Timepoint(s): Within 24 hours of birth 15. Spontaneous loss of pregnancy before 24 weeks of gestation (miscarriage), obtained directly from patient records and clinical notes; Timepoint(s): At 24 weeks of gestation 16. Implantation of fertilised egg outside the uterus (ectopic pregnancy), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 17. Intentional ending of pregnancy (termination of pregnancy), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 18. Initiation of breastfeeding within the first 48 hours postpartum, obtained directly from patient records and clinical notes; Timepoint(s): At 48 hours postpartum 19. Fetal death occurring at or after 24 weeks gestation (stillbirth), obtained directly from patient records and clinical notes; Timepoint(s): End of pregnancy 20. Death of a live-born infant within the first 28 days of life (neonatal death), obtained directly from patient records and clinical notes; Timepoint(s): Within the first 28 days of the infant's life 21. Presence of major structural or genetic abnormalities (congenital abnormalities), obtained directly from patient records and clinical notes; Timepoint(s): At birth 22. Birth occurring before 37 completed weeks of gestation (pre-term birth), obtained directly from patient records and clinical notes; Timepoint(s): At 37 weeks of gestation 23. Weight below the 10th percentile for gestational age at birth, obtained directly from patient records and clinical notes; Timepoint(s): At birth 24. APGAR score <7 at 1 and 5 minutes after birth, obtained directly from patient records and clinical notes; Timepoint(s): At 1 and 5 minutes after birth 25. Neonatal intensive care unit admission for any reason, obtained directly from patient records and clinical notes; Timepoint(s): At birth 26. Blood glucose level 5 mg/dL (2.5 mmol/L) in the first 24 hours of life (hypoglycaemia), obtained directly from patient records and clinical notes; Timepoint(s): In the first 24 hours of the infant’s life 27. Brain injury due to oxygen deprivation around the time of birth (hypoxic-ischemic encephalopathy), obtained directly from patient records and clinical notes; Timepoint(s): At birth 28. Percentage of all women with epilepsy in the intervention arm who receive EpiSafe intervention (REACH), obtained from medical records; Timepoint(s): End of intervention delivery 29. Percentage of booking midwives who complete the EpiSafe training (ADOPTION), obtained from training logs; Timepoint(s): End of intervention delivery 30. Patient and healthcare professional rating of EpiSafe bundle’s suitability for individual sites (APPROPRIATENESS); Timepoint(s): End of intervention delivery 31. Written protocol for management of (i) status epilepticus, (ii) epilepsy in pregnancy obtained from hospital documents; Timepoint(s): End of intervention delivery 32. Percentage of healthcare professionals caring for pregnant women with epilepsy trained in EpiSafe bundle, obtained from training log; Timepoint(s): End of intervention delivery 33. Number of multi-disciplinary team meetings discussing the high-risk women management, obtained from medical records; Timepoint(s): End of pregnancy 34. Implementation of regular audit and feedback cycles for care of epilepsy in pregnancy, obtained from quality improvement report; Timepoint(s): End of intervention delivery 35. Acceptability of the EpiSafe bundle to women, families, healthcare professionals measured via interviews; Timepoint(s): End of intervention delivery 36. Assessment of the EpiSafe bundle’s adaptability, feasibility and impact on health equity measured via interviews; Timepoint(s): End of intervention delivery 37. Identification of implementation barriers to intervention delivery and study conduct measured via interviews; Timepoint(s): End of intervention delivery 38. Patient reported experience measures (PREMs) on process of care: dignity, information, trust, positive birth experience measured via interviews; Timepoint(s): End of intervention delivery 39. Total cost associated with implementing the EpiSafe bundle measured via an economic evaluation; Timepoint(s): During pregnancy 40. Percentage of pregnant women with epilepsy who undergo a formal assessment of seizure risk and current anti-seizure medication during pregnancy, obtained from medical records; Timepoint(s): During pregnancy 41. Percentage of high-risk pregnant women on anti-seizure medication accessing specialist care within 2 weeks from referral, obtained from medical records; Timepoint(s): During pregnancy 42. Proportion of all women with epilepsy in whom discussion on risk-benefit of seizures and anti-seizure medications recorded during pregnancy, obtained from medical records; Timepoint(s): During pregnancy 43. Percentage of all pregnant women with epilepsy on anti-seizure medication who had a medication review in their first visit with the epilepsy specialist, obtained from medical records; Timepoint(s): At the first visit with an epilepsy specialist 44. Percentage of pregnant women with epilepsy who receive information on epilepsy in pregnancy; Timepoint(s): During pregnancy _____ Previous key secondary outcome(s): 1. The occurrence of any type of seizure, obtained directly from patient records and clinical notes (key secondary outcome); Timepoint(s): During pregnancy 2. Increase in the frequency or severity of seizures, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 3. Prolonged epileptic seizures lasting 30 minutes or a series of seizures with incomplete return of consciousness (status epilepticus), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 4. Death of pregnant women, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy or within 42 days of termination of pregnancy 5. Occurrence of epileptic seizures that result in altered consciousness, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 6. Accidents or injuries directly resulting from seizure activities, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 7. Any hospital admissions resulting from seizure activity during pregnancy, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 8. Admission to high dependency or intensive care unit for any reason, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 9. Anti-seizure medication adherence during pregnancy, obtained from care provider log; Timepoint(s): During pregnancy 10. Development of new-onset hypertension and proteinuria after 20 weeks of gestation (pre-eclampsia), obtained directly from patient records and clinical notes; Timepoint(s): After 20 weeks of gestation 11. Method of delivery (vaginal or caesarean), obtained directly from patient records and clinical notes; Timepoint(s): At time of delivery of baby 12. Onset of labour before 37 weeks of gestation, obtained directly from patient records and clinical notes; Timepoint(s): At 37 weeks of pregnancy 13. Rupture of membranes before the onset of labour, obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 14. Premature separation of the placenta from the uterine wall (placental abruption), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 15. Blood loss of 500 ml or more from the genital tract within 24 hours of birth (peripartum haemorrhage), obtained directly from patient records and clinical notes; Timepoint(s): Within 24 hours of birth 16. Spontaneous loss of pregnancy before 24 weeks of gestation (miscarriage), obtained directly from patient records and clinical notes; Timepoint(s): At 24 weeks of gestation 17. Implantation of fertilised egg outside the uterus (ectopic pregnancy), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 18. Intentional ending of pregnancy (termination of pregnancy), obtained directly from patient records and clinical notes; Timepoint(s): During pregnancy 19. Initiation of breastfeeding within the first 48 hours postpartum, obtained directly from patient records and clinical notes; Timepoint(s): At 48 hours postpartum 20. Fetal death occurring at or after 24 weeks gestation (stillbirth), obtained directly from patient records and clinical notes; Timepoint(s): End of pregnancy 21. Death of a live-born infant within the first 28 days of life (neonatal death), obtained directly from patient records and clinical notes; Timepoint(s): Within the first 28 days of the infant's life 22. Presence of major structural or genetic abnormalities (congenital abnormalities), obtained directly from patient records and clinical notes; Timepoint(s): At birth 23. Birth occurring before 37 completed weeks of gestation (pre-term birth), obtained directly from patient records and clinical notes; Timepoint(s): At 37 weeks of gestation 24. Weight below the 10th percentile for gestational age at birth, obtained directly from patient records and clinical notes; Timepoint(s): At birth 25. APGAR score <7 at 1 and 5 minutes after birth, obtained directly from patient records and clinical notes; Timepoint(s): At 1 and 5 minutes after birth 26. Neonatal intensive care unit admission for any reason, obtained directly from patient records and clinical notes; Timepoint(s): At birth 27. Blood glucose level 5 mg/dL (2.5 mmol/L) in the first 24 hours of life (hypoglycaemia) obtained directly from patient records and clinical notes; Timepoint(s): In the first 24 hours of the infant’s life 28. Need for neonatal resuscitation measures at birth, obtained directly from patient records and clinical notes; Timepoint(s): At birth 29. Brain injury due to oxygen deprivation around the time of birth (hypoxic-ischemic encephalopathy), obtained directly from patient records and clinical notes; Timepoint(s): At birth 30 Percentage of all women with epilepsy in the intervention arm who receive EpiSafe intervention (REACH), obtained from medical records; Timepoint(s): End of intervention delivery 31. Percentage of booking midwives who complete the EpiSafe training (ADOPTION), obtained from training logs; Timepoint(s): End of intervention delivery 32. Percentage of the components of the EpiSafe bundle delivered according to the protocol (FIDELITY), obtained from medical records; Timepoint(s): Over the duration of a maternity unit's involvement in the study 33. Number of components of the EpiSafe bundle adapted (ADAPTION), obtained from medical notes; Timepoint(s): Over the duration of a maternity unit's involvement in the study 34. Percentage of EpiSafe intervention components delivered (DOSE); Timepoint(s): Over the duration of a maternity unit's involvement in the study 35. Patient and healthcare professional rating of EpiSafe bundle’s suitability for individual sites (APPROPRIATENESS); Timepoint(s): End of intervention delivery 36. Written protocol for management of (i) status epilepticus, (ii) epilepsy in pregnancy obtained from hospital documents; Timepoint(s): End of intervention delivery 37. Percentage of healthcare professionals caring for pregnant women with epilepsy trained in EpiSafe bundle, obtained from training log; Timepoint(s): End of intervention delivery 38. Number of multi-disciplinary team meetings discussing the high-risk women management, obtained from medical records; Timepoint(s): End of pregnancy 39. Implementation of regular audit and feedback cycles for care of epilepsy in pregnancy, obtained from quality improvement report; Timepoint(s): End of intervention delivery 40. Acceptability of the EpiSafe bundle to women, families, healthcare professionals measured via interviews; Timepoint(s): End of intervention delivery Assessment of the EpiSafe bundle’s adaptability, feasibility and impact on health equity measured via interviews; Timepoint(s): End of intervention delivery 41. Identification of implementation barriers to intervention delivery and study conduct measured via interviews; Timepoint(s): End of intervention delivery 42. Patient reported experience measures (PREMs) on process of care: dignity, information, trust, positive birth experience measured via interviews; Timepoint(s): End of intervention delivery 43. Total cost associated with implementing the EpiSafe bundle measured via an economic evaluation; Timepoint(s): During pregnancy 44. Percentage of pregnant women with epilepsy who undergo a formal assessment of seizure risk and current anti-seizure medication during pregnancy, obtained from medical records; Timepoint(s): During pregnancy 45. Percentage of high-risk pregnant women on anti-seizure medication accessing specialist care within 2 weeks from referral, obtained from medical records; Timepoint(s): During pregnancy 46. Proportion of all women with epilepsy in whom discussion on risk-benefit of seizures and anti-seizure medications recorded during pregnancy, obtained from medical records; Timepoint(s): During pregnancy 47. Percentage of all pregnant women with epilepsy on anti-seizure medication who had a medication review in their first visit with the epilepsy specialist, obtained from medical records; Timepoint(s): At the first visit with an epilepsy specialist 48. Percentage of pregnant women with epilepsy who receive information on epilepsy in pregnancy; Timepoint(s): During pregnancy Old ethics approval format Approved 03/07/2025, West Midlands - Black Country Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, UK; +44 (0)207 104 8010; blackcountry.rec@hra.nhs.uk), ref: 25/WM/0109 10.1186/ISRCTN63771613 353310 CPMS: 68695, NIHR: 204156, Grant Code: 353310 68695 204156 Grant Code: Randomized; Both; Design type: Screening, Prevention, Process of Care, Management of Care, Qualitative Interventional Randomised controlled trial Treatment 2028-02-29T00:00:00.000Z United Kingdom England Scotland Mid Cheshire Hospitals NHS Foundation Trust

Leighton Hospital Leighton

Crewe England CW1 4QJ RBT@2.16.840.1.113883.2.1.3.2.4.18.48 Wirral University Teaching Hospital NHS Foundation Trust

Arrowe Park Hospital Arrowe Park Road Upton

Wirral England CH49 5PE RBL@2.16.840.1.113883.2.1.3.2.4.18.48 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 Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 Northumbria Healthcare NHS Foundation Trust

North Tyneside General Hospital Rake Lane

North Shields England NE29 8NH RTF@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital Kings Lynn

Gayton Road Queen Elizabeth Hospital Site

King's Lynn England PE30 4ET M5Z2Q@2.16.840.1.113883.2.1.3.2.4.18.48 York and Scarborough Teaching Hospitals NHS Foundation Trust

York Hospital Wigginton Road

York England YO31 8HE RCB@2.16.840.1.113883.2.1.3.2.4.18.48 Blackpool Teaching Hospitals NHS Foundation Trust

Victoria Hospital Whinney Heys Road

Blackpool England FY3 8NR RXL@2.16.840.1.113883.2.1.3.2.4.18.48 North Cumbria Integrated Care NHS Foundation Trust

Pillars Building Cumberland Infirmary Infirmary Street

Carlisle England CA2 7HY RNN@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals of Leicester NHS Trust

Leicester Royal Infirmary Infirmary Square

Leicester England LE1 5WW RWE@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Surrey County Hospital NHS Foundation Trust

Egerton Road

Guildford England GU2 7XX RA2@2.16.840.1.113883.2.1.3.2.4.18.48 Sandwell and West Birmingham Hospitals NHS Trust

Midland Metropolitan University Hos Grove Lane

Smethwick England B66 2QT RXK@2.16.840.1.113883.2.1.3.2.4.18.48 Worcestershire Acute Hospitals NHS Trust

Worcestershire Royal Hospital Charles Hastings Way

Worcester England WR5 1DD RWP@2.16.840.1.113883.2.1.3.2.4.18.48 Liverpool Women's NHS Foundation Trust

Liverpool Womens Hospital Crown Street

Liverpool England L8 7SS Y03020@2.16.840.1.113883.2.1.3.2.4.18.48 Grampian

Summerfield House 2 Eday Road

Aberdeen Scotland AB15 6RE SN9@2.16.840.1.113883.2.1.3.2.4.18.48 Ailsa Hospital

Dalmellington Road

Ayr Scotland KA6 6AB A201H@2.16.840.1.113883.2.1.3.8.2.16.2 Birmingham Women's and Children's NHS Foundation Trust

Steelhouse Lane

Birmingham England B4 6NH RQ3@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Victoria Infirmary

Claremont Wing Eye Dept Royal Victoria Infirmary Queen Victoria Road

Newcastle upon Tyne England NE1 4LP TP2WC@2.16.840.1.113883.2.1.3.2.4.18.48 Warrington and Halton Teaching Hospitals NHS Foundation Trust

Warrington Hospital Lovely Lane

Warrington England WA5 1QG RWW@2.16.840.1.113883.2.1.3.2.4.18.48 Walsall Healthcare NHS Trust

Manor Hospital Moat Road

Walsall England WS2 9PS RBK@2.16.840.1.113883.2.1.3.2.4.18.48 Ashford & St Peters Hospital

Guildford Road

Chertsey England KT16 0PZ NDA28@2.16.840.1.113883.2.1.3.2.4.18.48 Mid Cheshire Hospitals NHS Foundation Trust

Leighton Hospital Leighton

Crewe England CW1 4QJ RBT@2.16.840.1.113883.2.1.3.2.4.18.48 East Sussex Healthcare NHS Trust Hq

St. Annes House 729 the Ridge

St. Leonards-on-sea England TN37 7PT RXCHQ@2.16.840.1.113883.2.1.3.2.4.18.48 Frimley Health NHS Foundation Trust

Portsmouth Road Frimley

Camberley England GU16 7UJ RDU@2.16.840.1.113883.2.1.3.2.4.18.48 Guy's & St Thomas Hospital

Westminster Bridge Road

London England SE1 7EH 5LD99@2.16.840.1.113883.2.1.3.2.4.18.48 King's College Hospital

Denmark Hill

London England SE5 9RS 5LD98@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 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 Oxford University Hospitals NHS Foundation Trust

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RTH@2.16.840.1.113883.2.1.3.2.4.18.48 South Tees Hospitals NHS Foundation Trust

James Cook University Hospital Marton Road

Middlesbrough England TS4 3BW RTR@2.16.840.1.113883.2.1.3.2.4.18.48 South Tyneside and Sunderland NHS Foundation Trust

Sunderland Royal Hospital Kayll Road

Sunderland England SR4 7TP R0B@2.16.840.1.113883.2.1.3.2.4.18.48 The Shrewsbury and Telford Hospital NHS Trust

Mytton Oak Road

Shrewsbury England SY3 8XQ RXW@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Sussex NHS Foundation Trust

Worthing Hospital Lyndhurst Road

Worthing England BN11 2DH RYR@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital Mindelsohn Way Edgbaston

Birmingham England B15 2GW RRK@2.16.840.1.113883.2.1.3.2.4.18.48 Epsom and St Helier University Hospitals NHS Trust

St Helier Hospital Wrythe Lane

Carshalton England SM5 1AA RVR@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 Patient Unit-level inclusion criteria: NHS maternity units providing antenatal care for pregnant women with epilepsy, with a pathway to access specialist antenatal epilepsy care Individual level inclusion criteria: All pregnant women >=18 years of age with a confirmed diagnosis of epilepsy, attending antenatal booking visit at participating maternity units in their first trimester Mixed 18 Years 120 Years Female 1866 0 Current key exclusion criteria as of 23/02/2026: Unit-level exclusion criteria, maternity units: 1. Where there is no access to dedicated epilepsy specialists (either obstetric or neurological) 2. That lack the resources to implement the EpiSafe bundle 3. Where procedures are already in place for all women with epilepsy to access specialist epilepsy care <14 weeks' gestation Individual level exclusion criteria, pregnant women: 1. With non-epileptic attack disorder (NEAD) 2. Whose epilepsy diagnosis was not confirmed before pregnancy 3. Less than 18 years of age 4. Withdrawal of consent to use data, through the NHS data opt-out _____ Previous key exclusion criteria: Unit-level exclusion criteria, maternity units: 1. Where there is no access to dedicated epilepsy specialists (either obstetric or neurological) 2. That lack the resources to implement the EpiSafe bundle 3. Where procedures are already in place for all women with epilepsy to access specialist epilepsy care <14 weeks' gestation Individual level exclusion criteria, pregnant women: 1. With non-epileptic attack disorder (NEAD) 2. Whose epilepsy diagnosis was not confirmed before pregnancy 3. Who had already seen or are planning to see an epilepsy specialist in the first trimester 4. Less than 18 years of age 5. Withdrawal of consent to use data, through the NHS data opt-out 2025-09-11T00:00:00.000Z 2027-06-30T00:00:00.000Z Pregnant women with epilepsy Pregnancy and Childbirth Maternity units will be randomised to either an intervention or control arm in a 1:1 ratio. All women receiving antenatal care in a specific maternity unit (cluster) will receive the same care according to the allocation of the cluster. Intervention arm: EpiSafe bundle The EpiSafe bundle incorporates a structured risk assessment and implementation strategies to facilitate identification and referral of high-risk pregnant women with epilepsy for early specialist epilepsy care. Booking midwives will use the EpiSafe bundle during the antenatal booking visit (first antenatal appointment) of pregnant women with epilepsy. Control arm: Usual care Pregnant women will be booked for their usual care according to existing National Institute for Health and Care Excellence (NICE) and Royal College of Obstetricians and Gynaecologists guidelines. In both arms, women will be followed up until the end of pregnancy. Other Anonymised data generated during the trial may be shared with a qualified third party upon request. Data requests will be considered by the CI (Prof Shakila Thangaratinam; s.thangaratinam@liverpool.ac.uk) and the sponsor (sponsor@liverpool.ac.uk). For approved requests, the dataset will be prepared by the coordinating centre and will be provided as a summary at a cluster and study level only. A data-sharing agreement will be required between the sponsor and the external party. Available on request

Study website Migrated from study website field

151bbc61-a2b6-42e9-9f1f-c6b88d2ed178 a320c1fa-8320-4bbf-a869-f595b7ebec22 36d9a2b1-bba5-4469-baa5-fbaac0e6716f dcbd2740-623e-421a-92ed-ad61fb1646d1 Yes Carmel Moore https://orcid.org/0000-0002-2386-7200 Public

Anglia Ruskin University Faculty of Health, Education, Medicine, and Social Care Bishops Hall Lane

Chelmsford United Kingdom CM1 1SQ +44 (0)1245 684938 carmel.moore@aru.ac.uk Public John Allotey https://orcid.org/0000-0003-4134-6246 Scientific

University of Liverpool Department of Epidemiology and Women’s Health William Henry Duncan Building 6 West Derby Street

Liverpool United Kingdom L7 8TX - john.allotey@liverpool.ac.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 92742608 true The ROSIER trial: requirement for surgical intervention after endoscopic retrograde cholangiopancreatography ROSIER Following endoscopic retrograde cholangiopancreatography (ERCP), treatment with expectant management (managed with the intention of not undergoing cholecystectomy) is non-inferior to laparoscopic cholecystectomy in patients with common bile duct stones. Background and study aims This study aims to improve treatment for patients after gallstones (common bile duct stones). We want to find out if patients benefit from having their gallbladder removed after gallstone treatment. Gallstones are solid deposits that form in the gallbladder. When these stones move into the bile duct, they can cause pain and lead to complications, often needing urgent medical treatment. Each year, around 20,000 endoscopic retrograde cholangiopancreatography (ERCP) procedures are performed in England to remove these stones. After ERCP, patients are usually advised to talk to a surgeon about the possible removal of their gallbladder to prevent future complications from gallstones. Although the National Institute for Health and Care Excellence (NICE) recommends this surgery, practice varies a lot, and nearly half of patients who are eligible for surgery don’t have an operation. This inconsistency means that around half of the patients could either be under- or over-treated. We need more evidence to confirm which approach is best for patients. Who can participate? Adult patients aged 18 years and over who have recently had bile duct stones cleared from their bile duct and are considered fit for surgery. What does the study involve? Participants will be randomly assigned to one of two groups. Half of the participants will be in the surgery group and have an operation to remove their gallbladder. The other half will be in the expectant management group, who will not have a scheduled operation to remove their gallbladder. Instead, they will be monitored by their healthcare team (with no intention of undergoing gallbladder-removal surgery). All participants will be followed up for 2 years from when they enter the study. Clinical data will be collected about participants when they enter the study and then at 3, 6, 12 and 24 months afterwards. Participants will be asked to complete a set of quality of life questionnaires when they enter the study and then every three months for 2 years. In between the 3-monthly questionnaires, participants will also be asked to complete a short questionnaire each month about their pain. Some study data will be collected from Hospital Episode Statistics, a standard NHS registry. For randomly selected participants, copies of their scans and reports from the procedure they had done to remove their bile duct gallstones prior to study entry will be collected by the study team for central review purposes. Interviews will take place with some of the patients who were approached for the ROSIER study, to find out why they chose to take part in the study or not. Interviews will also be carried out with participating hospital staff to find out their views about the study and the study processes. What are the possible benefits and risks of participating? We don’t know if participants will personally benefit from taking part in this research, but it is possible. As the research involves treatments that participants could get in standard care, we don’t anticipate there being any extra risk to participants from taking part in the study. For participants who have gallbladder-removal surgery during their participation in the study, the operation would be performed as per local routine care. Therefore, the risks of undergoing this procedure would be the same both inside and outside of the study. Where is the study run from? The study is being run from the Clinical Trials Research Unit at the University of Leeds in the UK. When is the study starting and how long is it expected to run for? June 2024 to September 2030 Who is funding the study? The study is funded by the National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? 1. Rachel Kelly (Senior Trial Coordinator), ROSIER@leeds.ac.uk 2. Mr Andrew Smith, andrewmsmith@nhs.net 3. Prof. Giles Toogood, giles.toogood@nhs.net Patient-reported pain, defined by the area under the curve (AUC) of the SF-36 bodily pain domain within 24 months of randomisation. This will be assessed monthly over the 24-month post-randomisation period. 1. Overall patient wellbeing measured using the condition-specific Otago Gallstones Condition Specific Questionnaire (CSQ) every 3 months up to 24 months post-randomisation 2. SF-36 physical functioning, physical role limitations, general health perceptions, energy/vitality, social functioning, emotional, and mental health domains, assessed every 3 months for up to 24 months post-randomisation 3. Adverse events occurring within 24 months post-randomisation 4. Subsequent disease or intervention-related surgeries occurring within 24 months post-randomisation 5. Number and timing of readmissions (for biliary events, complications and treatment) occurring within 24 months of randomisation, derived from Hospital Episode Statistics (HES) data 6. Cost-utility as measured by the EQ-5D-5L and health care resource use questionnaires assessed every 3 months up to 24 months post-randomisation 7. All-cause mortality within 24 months post-randomisation Exploratory outcome measure: Identifying potential risk factors that may predict the need for laparoscopic cholecystectomy within 24 months of randomisation to expectant management. Potential risk factors that may be explored will include, but are not necessarily limited to, age, sex, BMI, cholangitis, obstructive jaundice without sepsis, pancreatitis, biliary pain or colic, cholecystitis, previous abdominal surgery, bile duct related factors (stone size, number of stones, duct size, obstruction in Hartmann’s pouch), and gallbladder wall thickness on ultrasound. Full details of risk factors to be explored will be detailed a priori in the statistical analysis plan. Old ethics approval format Approved 13/03/2025, London - Bloomsbury Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, UK; +44 (0)207 104 8384, +44 (0)207 104 8256, +44 (0)207 104 8276; bloomsbury.rec@hra.nhs.uk), ref: 25/LO/0110 10.1186/ISRCTN92742608 333432 CPMS: 58170, NIHR: 159585 333432 58170 159585 Randomized; Interventional; Design type: Treatment, Surgery, Active Monitoring Interventional Randomised controlled trial Treatment 2030-09-30T00:00:00.000Z United Kingdom England 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 University of Leeds

Woodhouse Lane

Leeds England LS2 9JT University Hospital Southampton NHS Foundation Trust

Southampton General Hospital Tremona Road

Southampton England SO16 6YD RHM@2.16.840.1.113883.2.1.3.2.4.18.48 Somerset NHS Foundation Trust

Trust Management Lydeard House Musgrove Park Hospital

Taunton England TA1 5DA RH5@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Plymouth NHS Trust

Derriford Hospital Derriford Road Derriford

Plymouth England PL6 8DH RK9@2.16.840.1.113883.2.1.3.2.4.18.48 Hampshire Hospitals NHS Foundation Trust

Basingstoke and North Hampshire Hos Aldermaston Road

Basingstoke England RG24 9NA RN5@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals of Derby and Burton NHS Foundation Trust

Royal Derby Hospital Uttoxeter Road

Derby England DE22 3NE RTG@2.16.840.1.113883.2.1.3.2.4.18.48 The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTD@2.16.840.1.113883.2.1.3.2.4.18.48 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 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 East Suffolk and North Essex NHS Foundation Trust

Colchester Dist General Hospital Turner Road

Colchester England CO4 5JL RDE@2.16.840.1.113883.2.1.3.2.4.18.48 North Bristol NHS Trust

Southmead Hospital Southmead Road Westbury-on-trym

Bristol England BS10 5NB RVJ@2.16.840.1.113883.2.1.3.2.4.18.48 Nottingham University Hospitals NHS Trust

Trust Headquarters Queens Medical Centre Derby Road

Nottingham England NG7 2UH RX1@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 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 North Tees and Hartlepool NHS Foundation Trust

University Hospital of Hartlepool Holdforth Road

Hartlepool England TS24 9AH RVW@2.16.840.1.113883.2.1.3.2.4.18.48 York and Scarborough Teaching Hospitals NHS Foundation Trust

York Hospital Wigginton Road

York England YO31 8HE RCB@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 22/07/2026: 1. Aged ≥18 years 2. Undergone ERCP, sphincterotomy and duct clearance for common bile duct stones 3. Fit for and willing to undergo laparoscopic or robotic cholecystectomy 4. Able and willing to provide written informed consent 5. Able & willing to comply with the terms of the protocol, including completion of QoL questionnaires 6. Suitable for expectant management (in the opinion of the local investigator) Previous inclusion criteria: 1. Aged >=18 years 2. Undergone ERCP, sphincterotomy and duct clearance for common bile duct stones 3. Fit for and willing to undergo laparoscopic or robotic cholecystectomy 4. Able and willing to provide written informed consent 5. Able and willing to comply with the terms of the protocol, including completion of QoL questionnaires Mixed 18 Years 100 Years All 1318 0 Current exclusion criteria as of 22/07/2026: 1. Pregnancy or planned pregnancy 2. Gallbladder complications requiring urgent intervention, e.g., cholecystostomy insertion or endoscopic gallbladder drainage 3. Undergone previous cholecystectomy 4. Common bile duct stent in situ (unless biodegradable) 5. Pancreatic duct stent in situ (unless biodegradable) Previous exclusion criteria: 1. Pregnancy or planned pregnancy 2. Evidence of empyema or perforated gallbladder requiring urgent intervention 3. Cholecystostomy insertion 4. Undergone previous cholecystectomy 2025-06-27T00:00:00.000Z 2027-08-31T00:00:00.000Z Common bile duct stones Digestive System Current interventions as of 23/07/2026: ROSIER is an IDEAL stage 3, multicentre, pragmatic, unblinded, two-arm individually randomised controlled non-inferiority trial with an embedded group-sequential interim analysis to evaluate the effectiveness and cost-effectiveness of expectant management (EM) compared with laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography (ERCP) for clearance of gallstones from the common bile duct. Expectant management means monitoring patients with the intention of not having surgery. Laparoscopic cholecystectomy is a keyhole operation to remove the gallbladder. Both treatment options are available to patients in routine NHS care. A 12-month internal pilot phase will assess recruitment feasibility and an integrated qualitative sub-study will assess: a) factors influencing trial participation, including willingness to randomise and be randomised b) experiences of the study interventions and process, c) factors likely to influence wider implementation of study findings. Trial population: The main trial will recruit 1318 adult participants, aged ≥ 18 years who have undergone ERCP, sphincterotomy and duct clearance for common bile duct stones who are fit to undergo surgery. Participants must be able and willing to give written informed consent and be able and willing to comply with the terms of the protocol, including completion of quality of life questionnaires. Site eligibility: The trial will open in approximately 33 NHS research sites across the UK. To be eligible to participate in the trial, research sites must meet the following criteria: 1. Be a secondary or tertiary care centre offering laparoscopic cholecystectomy 2. Offer ERCP 3. Have the anticipated capacity to recruit approximately 1-2 participants per month Participant identification and consent (main trial): Patients who have undergone ERCP, sphincterotomy and duct clearance for common bile duct stones will be screened for eligibility at participating research sites. Patients will be approached for possible recruitment into the trial following completion of ERCP for duct clearance and once they are considered fit for surgery. Suitability for inclusion in the trial will be assessed according to the trial eligibility criteria and patients will be provided with verbal and written details. A verbal explanation of the trial along with the approved Participant Information Sheet (PIS), will be provided by a suitably qualified member of the healthcare team for the patient to consider. The PIS will provide detailed information about the rationale, design and personal implications of the study. A PIS Supplementary Information Document, containing additional information about the trial, will also be provided to the participant. Reading the Supplementary Information Sheet is optional for patients and they do not need to read this document in order to consent to the ROSIER trial, if they do not wish to do so. Following information provision, patients will be given the opportunity to discuss the trial with their family and medically qualified members of the healthcare team before they are asked whether they would be willing to take part in the trial. Patients will be given as long as they need to consider participation in the trial, ideally this will be at least 24 hours. The right of the patient to refuse consent without giving reasons will be respected. Patients who wish to participate will be invited to provide written informed consent including explicit consent for the transfer of a copy of their signed consent form to the CTRU. Following consent patients will be formally assessed for eligibility. Informed consent may only be obtained by the Principal Investigator (PI) or an appropriate, delegated, healthcare professional or Clinical Research Practitioner. The healthcare professional/Clinical Research Practitioner must have knowledge of the trial interventions and have received training in the principles of GCP and the Declaration of Helsinki 1996. The healthcare professional/Clinical Research Practitioner must be fully trained in the trial according to the ethically approved protocol and be authorised and approved by the PI to take informed consent as documented in the trial Authorised Personnel Log. Randomisation: Participants will be randomised on an equal basis, using a computer-generated minimisation algorithm incorporating a random element, to undergo either expectant management or laparoscopic cholecystectomy. Randomisation will be based on a minimisation algorithm with random component, ensuring that treatment groups will be balanced for the following minimisation factors: • Cholangitis prior to ERCP (yes, no) • Obstructive jaundice without sepsis prior to ERCP (yes, no) • Pancreatitis prior to ERCP (yes, no) • Biliary pain or colic prior to ERCP (yes, no) • Cholecystitis prior to ERCP (yes, no) • Randomising Trust (derived from randomising site) Pre-operative investigations (only applicable to patients who undergo laparoscopic cholecystectomy): For participants who have laparoscopic cholecystectomy (LC), pre-operative investigations and preparation will be as per institutional protocol. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. Interventions: Laparascopic cholecystectomy: For participants undergoing laparoscopic cholecystectomy, the operation should be performed as per institutional protocol, and by whichever surgeon would ordinarily carry out the procedure according to the local standard of care. LC may be performed using a laparoscopic or robotic approach. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. Expectant management: EM participants will be managed with the intention of not undergoing cholecystectomy. EM will be at the discretion of the surgical team and according to local practice. During follow-up, if there is a clinical change, and it is clinically appropriate, surgery may occur as part of this treatment. If an EM patient requires LC for a clinically valid reason, for example, severe biliary pain, this will be compliant with the randomised treatment allocation. The participant will continue to be followed up until 24 months post-randomisation. Post-operative care (only applicable to participants who undergo laparoscopic cholecystectomy): For participants undergoing LC, post-operative care will be as per institutional protocol. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. All participants (regardless of trial arm) will be followed up for trial purposes for 24 months post-randomisation. Trial follow-up: Clinical assessments: All participants will undergo a clinical review for trial purposes at 3, 6, 12 and 24 months post-randomisation. The trial follow-up assessments can be done via telephone if the participant is not due to be seen in clinic as part of local standard care at these timepoints, and will likely take around 15 minutes. Data collected at the clinical follow-ups will include (but will not be limited to): • Assessment details • Adverse events and severity • Need for further biliary intervention Any further clinical assessments/visits will be according to local standard clinical practice. Participant-completed questionnaires (3-monthly): Participants will complete a number of questionnaires designed to capture health-related quality of life and the costs involved with each treatment. All participants will complete the health-related quality of life questionnaire packs at baseline and then 3-monthly up to and including 24 months post-randomisation. Each questionnaire pack will consist of three validated questionnaires and a Health and Social Care Resource Use questionnaire, and will take approximately 30 minutes to complete. The baseline questionnaires will be administered to the participants by the local site research team and completed on paper. The baseline questionnaires should be completed after informed consent but prior to randomisation, or at least before the participant is informed of their randomisation result. The follow-up questionnaires will be administered directly to participants by the ROSIER CTRU trial team by SMS, email or post (depending on the participant's QoL completion preferences). If participants choose to complete their follow-up questionnaires in paper format via post, a freepost envelope will be provided so that they can return their completed questionnaire pack to the CTRU. Should a completed questionnaire not be received at the CTRU by the required time-point, the CTRU will send one reminder to the participant either by post, SMS or email (depending on the participant’s questionnaire-completion preferences). Monthly pain questionnaire: Participants will be asked to complete a short pain questionnaire, consisting of the two bodily pain domain questions of the SF36 survey, on a monthly basis in between the 3-monthly questionnaire packs throughout the 24-month follow-up period. The monthly pain questionnaire will ideally be completed by participants via SMS to minimise research burden, but participants will also have the option of completing this via email or on paper (via diary card), if they'd prefer. For paper completers, the diary card on which they can record their monthly pain responses for the next two months will be sent out alongside the 3-monthly questionnaire packs. Participants will then be able to return their completed diary card for the previous two months with their next 3-monthly pack. Pre-paid addressed envelopes will be provided for the return of the paper QoL questionnaires to CTRU. ERCP Central Review: As part of the trial eligibility criteria, all participants must have undergone ERCP (as per local standard practice) prior to being recruited to the ROSIER trial. ERCP details will be collected for all participants on the trial electronic case report forms. To validate the ERCP dataset, 10% of randomly selected occlusion cholangiogram images (taken during ERCP) and reports will be collected by the CTRU for central review. Hospital Episode Statistics (HES) Data Collection: Hospital admission data: Details of hospital admissions for biliary events, complications or treatment within 24 months of randomisation will be obtained from HES data. The CTRU trial team will submit a data access request to HES to obtain this data so there is no input required from sites. Readmissions (longer-term follow-up data): It is planned that late readmissions for biliary events, complications and treatment within 10 years post-randomisation will be derived from HES data. A separate ethics application and protocol will be submitted for this planned element of the research at an appropriate timepoint in the future. However, consent to collect the longer-term follow-up HES data will be obtained from trial participants from the outset as part of the main trial consent process - this is covered in the ROSIER Participant Information Sheet and Informed Consent Form. Qualitative sub-study: The qualitative sub-study incorporates mixed qualitative methods including interviews with patients and health professionals and audio-recording of recruitment conversations. Data collection and analysis will commence during study set-up and will focus on the internal pilot. The approach will be flexible and respond to project needs at the different stages of the trial. A summary of the activities in the sub-study is given below: Site survey: All participating sites will be asked to describe their current organisation of care for patients with bile duct stones (e.g. number of surgeons involved; number of procedures annually), including expectant management and perioperative LC management, and including any written information for patients. This will inform the purposive sample. Interviews with patients declining trial participation (during internal pilot only): During the internal pilot phase, patients (n = 10-12) who are approached for the ROSIER trial but decline to participate will be invited to take part in a single qualitative interview, which is anticipated to take around 45 minutes. Interviews with trial consenters (throughout the trial): Throughout the trial, a subset of participants who consent to take part in the ROSIER trial will be invited to take part in a qualitative interview (n = 24-28). Research site staff will invite all participants to consent to contact as part of the informed consent process for the main trial. Some patients may be asked to do a second interview to follow their experience over time. No patient will be asked to do more than two interviews. Each interview is anticipated to take approximately 45 minutes. To better understand patients' experience over time we will invite patients to contribute photos that communicate their experience of treatment or symptoms of bile duct stones (photo-elicitation). This will be optional. An amendment will be submitted for the materials relating to this element of the research prior to photos being requested from participants. Interviews with patients (both main trial consenters and decliners) will take place via telephone or video chat (e.g., via Microsoft Teams or Zoom). With permission from participants, the interviews will be audio-recorded, using digital encrypted recorders, or via the secure digital platform for interviews conducted virtually. Interviews with healthcare professionals (throughout the trial): Interviews with healthcare professionals involved in recruitment to ROSIER or in delivering the trial interventions(n = 24-30) will take place throughout the trial and are anticipated to take around 45 minutes each time. Most of the healthcare professional interviews will be done via telephone/virtual video conferencing platform (Microsoft Teams or Zoom), although some may be done face to face (for example, to coincide with a site observation). With permission from participants, the interviews will be audio-recorded, using digital encrypted recorders, or via the secure digital platform for interviews conducted virtually. GP focus groups: Two focus groups with GPs will be undertaken to understand primary care perspectives of the trial arms. Topic guides will be developed based on the initial findings from the ROSIER hospital health professional/patient interviews and will be submitted, with the relevant recruitment and consent materials, as an amendment. Audio recording of recruitment conversations: Sites taking part in the internal pilot will be asked to record their recruitment conversations with potential participants. A purposive sample of sites during the main trial (e.g. those struggling to recruit) will also be recruited (n= approximately 150 recordings in total across all sites - approximately 10 per site). Observation of ROSIER meetings (e.g. Site Initiation Visits and investigator meetings): It is planned that qualitative researchers will attend ROSIER meetings such as Site Initiation Visits and investigator meetings and make notes of points raised. During the internal pilot, site set-up meetings will be conducted to map trial and clinical pathways. Analysis will incorporate rapid qualitative analysis (during internal pilot); pen portrait and thematic analysis approaches and will be informed by Normalisation Process Theory. Timetable for research: There will be a 30-month recruitment period and all participants will be followed up until 24 months post-randomisation. The qualitative sub-study will run throughout the trial. One-sided superiority testing will be performed at two stages: in an interim analysis and at the full sample size of 1318 participants, prior to the non-inferiority analysis. The interim superiority analysis is estimated to require 530 participants with complete data – i.e., 664 (332 per arm) participants, assuming 20% attrition. Should superiority be demonstrated at either of these two stages the trial will close. The end of the trial is defined as the last participant's last data item within the 24-month follow-up period. _____ Previous interventions: ROSIER is an IDEAL stage 3, multicentre, pragmatic, unblinded, two-arm individually randomised controlled non-inferiority trial with an embedded group-sequential interim analysis to evaluate the effectiveness and cost-effectiveness of expectant management (EM) compared with laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography (ERCP) for clearance of gallstones from the common bile duct. Expectant management means monitoring patients with the intention of not having surgery. Laparoscopic cholecystectomy is a keyhole operation to remove the gallbladder. Both treatment options are available to patients in routine NHS care. A 12-month internal pilot phase will assess recruitment feasibility and an integrated qualitative sub-study will assess: a) factors influencing trial participation, including willingness to randomise and be randomised b) experiences of the study interventions and process, c) factors likely to influence wider implementation of study findings. Trial population: The main trial will recruit 1318 adult participants, aged ≥ 18 years who have undergone ERCP, sphincterotomy and duct clearance for common bile duct stones who are fit to undergo surgery. Participants must be able and willing to give written informed consent and be able and willing to comply with the terms of the protocol, including completion of quality of life questionnaires. Site eligibility: The trial will open in approximately 33 NHS research sites across the UK. To be eligible to participate in the trial, research sites must meet the following criteria: 1. Be a secondary or tertiary care centre offering laparoscopic cholecystectomy 2. Offer ERCP 3. Have the anticipated capacity to recruit approximately 1-2 participants per month Participant identification and consent (main trial): Patients who have undergone ERCP, sphincterotomy and duct clearance for common bile duct stones will be screened for eligibility at participating research sites. Patients will be approached for possible recruitment into the trial following completion of ERCP for duct clearance and once they are considered fit for surgery. Suitability for inclusion in the trial will be assessed according to the trial eligibility criteria and patients will be provided with verbal and written details. A verbal explanation of the trial along with the approved Participant Information Sheet (PIS), will be provided by a suitably qualified member of the healthcare team for the patient to consider. The PIS will provide detailed information about the rationale, design and personal implications of the study. A PIS Supplementary Information Document, containing additional information about the trial, will also be provided to the participant. Reading the Supplementary Information Sheet is optional for patients and they do not need to read this document in order to consent to the ROSIER trial, if they do not wish to do so. Following information provision, patients will be given the opportunity to discuss the trial with their family and medically qualified members of the healthcare team before they are asked whether they would be willing to take part in the trial. Patients will be given as long as they need to consider participation in the trial, ideally this will be at least 24 hours. The right of the patient to refuse consent without giving reasons will be respected. Patients who wish to participate will be invited to provide written informed consent including explicit consent for the transfer of a copy of their signed consent form to the CTRU. Following consent patients will be formally assessed for eligibility. Informed consent may only be obtained by the Principal Investigator (PI) or an appropriate, delegated, healthcare professional or Clinical Research Practitioner. The healthcare professional/Clinical Research Practitioner must have knowledge of the trial interventions and have received training in the principles of GCP and the Declaration of Helsinki 1996. The healthcare professional/Clinical Research Practitioner must be fully trained in the trial according to the ethically approved protocol and be authorised and approved by the PI to take informed consent as documented in the trial Authorised Personnel Log. Randomisation: Participants will be randomised on an equal basis, using a computer-generated minimisation algorithm incorporating a random element, to undergo either expectant management or laparoscopic cholecystectomy. Randomisation will be based on a minimisation algorithm with random component, ensuring that treatment groups will be balanced for the following minimisation factors: • Cholangitis prior to ERCP (yes, no) • Obstructive jaundice without sepsis prior to ERCP (yes, no) • Pancreatitis prior to ERCP (yes, no) • Biliary pain or colic prior to ERCP (yes, no) • Cholecystitis prior to ERCP (yes, no) • Randomising site Pre-operative investigations (only applicable to patients who undergo laparoscopic cholecystectomy): For participants who have laparoscopic cholecystectomy (LC), pre-operative investigations and preparation will be as per institutional protocol. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. Interventions: Laparascopic cholecystectomy: For participants undergoing laparoscopic cholecystectomy, the operation should be performed as per institutional protocol, and by whichever surgeon would ordinarily carry out the procedure according to the local standard of care. LC may be performed using a laparoscopic or robotic approach. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. Expectant management: EM participants will be managed with the intention of not undergoing cholecystectomy. EM will be at the discretion of the surgical team and according to local practice. During follow-up, if there is a clinical change, and it is clinically appropriate, surgery may occur as part of this treatment. If an EM patient requires LC for a clinically valid reason, for example, severe biliary pain, this will be compliant with the randomised treatment allocation. The participant will continue to be followed up until 24 months post-randomisation. Post-operative care (only applicable to participants who undergo laparoscopic cholecystectomy): For participants undergoing LC, post-operative care will be as per institutional protocol. This applies to all participants who undergo LC during their participation in the trial, whether they were randomised to the LC arm and have surgery, or they were randomised to expectant management but undergo LC. All participants (regardless of trial arm) will be followed up for trial purposes for 24 months post-randomisation. Trial follow-up: Clinical assessments: All participants will undergo a clinical review for trial purposes at 3, 6, 12 and 24 months post-randomisation. The trial follow-up assessments can be done via telephone if the participant is not due to be seen in clinic as part of local standard care at these timepoints, and will likely take around 15 minutes. Data collected at the clinical follow-ups will include (but will not be limited to): • Assessment details • Adverse events and severity • Need for further biliary intervention Any further clinical assessments/visits will be according to local standard clinical practice. Participant-completed questionnaires (3-monthly): Participants will complete a number of questionnaires designed to capture health-related quality of life and the costs involved with each treatment. All participants will complete the health-related quality of life questionnaire packs at baseline and then 3-monthly up to and including 24 months post-randomisation. Each questionnaire pack will consist of three validated questionnaires and a Health and Social Care Resource Use questionnaire, and will take approximately 30 minutes to complete. The baseline questionnaires will be administered to the participants by the local site research team and completed on paper. The baseline questionnaires should be completed after informed consent but prior to randomisation, or at least before the participant is informed of their randomisation result. The follow-up questionnaires will be administered directly to participants by the ROSIER CTRU trial team by SMS, email or post (depending on the participant's QoL completion preferences). If participants choose to complete their follow-up questionnaires in paper format via post, a freepost envelope will be provided so that they can return their completed questionnaire pack to the CTRU. Should a completed questionnaire not be received at the CTRU by the required time-point, the CTRU will send one reminder to the participant either by post, SMS or email (depending on the participant’s questionnaire-completion preferences). Monthly pain questionnaire: Participants will be asked to complete a short pain questionnaire, consisting of the two bodily pain domain questions of the SF36 survey, on a monthly basis in between the 3-monthly questionnaire packs throughout the 24-month follow-up period. The monthly pain questionnaire will ideally be completed by participants via SMS to minimise research burden, but participants will also have the option of completing this via email or on paper (via diary card), if they'd prefer. For paper completers, the diary card on which they can record their monthly pain responses for the next two months will be sent out alongside the 3-monthly questionnaire packs. Participants will then be able to return their completed diary card for the previous two months with their next 3-monthly pack. Pre-paid addressed envelopes will be provided for the return of the paper QoL questionnaires to CTRU. ERCP Central Review: As part of the trial eligibility criteria, all participants must have undergone ERCP (as per local standard practice) prior to being recruited to the ROSIER trial. ERCP details will be collected for all participants on the trial electronic case report forms. To validate the ERCP dataset, 10% of randomly selected occlusion cholangiogram images (taken during ERCP) and reports will be collected by the CTRU for central review. Hospital Episode Statistics (HES) Data Collection: Hospital admission data: Details of hospital admissions for biliary events, complications or treatment within 24 months of randomisation will be obtained from HES data. The CTRU trial team will submit a data access request to HES to obtain this data so there is no input required from sites. Readmissions (longer-term follow-up data): It is planned that late readmissions for biliary events, complications and treatment within 10 years post-randomisation will be derived from HES data. A separate ethics application and protocol will be submitted for this planned element of the research at an appropriate timepoint in the future. However, consent to collect the longer-term follow-up HES data will be obtained from trial participants from the outset as part of the main trial consent process - this is covered in the ROSIER Participant Information Sheet and Informed Consent Form. Qualitative sub-study: The qualitative sub-study incorporates mixed qualitative methods including interviews with patients and health professionals and audio-recording of recruitment conversations. Data collection and analysis will commence during study set-up and will focus on the internal pilot. The approach will be flexible and respond to project needs at the different stages of the trial. A summary of the activities in the sub-study is given below: Site survey: All participating sites will be asked to describe their current organisation of care for patients with bile duct stones (e.g. number of surgeons involved; number of procedures annually), including expectant management and perioperative LC management, and including any written information for patients. This will inform the purposive sample. Interviews with patients declining trial participation (during internal pilot only): During the internal pilot phase, patients (n = 10-12) who are approached for the ROSIER trial but decline to participate will be invited to take part in a single qualitative interview, which is anticipated to take around 45 minutes. Interviews with trial consenters (throughout the trial): Throughout the trial, a subset of participants who consent to take part in the ROSIER trial will be invited to take part in a qualitative interview (n = 24-28). Research site staff will invite all participants to consent to contact as part of the informed consent process for the main trial. Some patients may be asked to do a second interview to follow their experience over time. No patient will be asked to do more than two interviews. Each interview is anticipated to take approximately 45 minutes. To better understand patients' experience over time we will invite patients to contribute photos that communicate their experience of treatment or symptoms of bile duct stones (photo-elicitation). This will be optional. An amendment will be submitted for the materials relating to this element of the research prior to photos being requested from participants. Interviews with patients (both main trial consenters and decliners) will take place via telephone or video chat (e.g., via Microsoft Teams or Zoom). With permission from participants, the interviews will be audio-recorded, using digital encrypted recorders, or via the secure digital platform for interviews conducted virtually. Interviews with healthcare professionals (throughout the trial): Interviews with healthcare professionals involved in recruitment to ROSIER or in delivering the trial interventions(n = 24-30) will take place throughout the trial and are anticipated to take around 45 minutes each time. Most of the healthcare professional interviews will be done via telephone/virtual video conferencing platform (Microsoft Teams or Zoom), although some may be done face to face (for example, to coincide with a site observation). With permission from participants, the interviews will be audio-recorded, using digital encrypted recorders, or via the secure digital platform for interviews conducted virtually. GP focus groups: Two focus groups with GPs will be undertaken to understand primary care perspectives of the trial arms. Topic guides will be developed based on the initial findings from the ROSIER hospital health professional/patient interviews and will be submitted, with the relevant recruitment and consent materials, as an amendment. Audio recording of recruitment conversations: Sites taking part in the internal pilot will be asked to record their recruitment conversations with potential participants. A purposive sample of sites during the main trial (e.g. those struggling to recruit) will also be recruited (n= approximately 150 recordings in total across all sites - approximately 10 per site). Observation of ROSIER meetings (e.g. Site Initiation Visits and investigator meetings): It is planned that qualitative researchers will attend ROSIER meetings such as Site Initiation Visits and investigator meetings and make notes of points raised. During the internal pilot, site set-up meetings will be conducted to map trial and clinical pathways. Analysis will incorporate rapid qualitative analysis (during internal pilot); pen portrait and thematic analysis approaches and will be informed by Normalisation Process Theory. Timetable for research: There will be a 30-month recruitment period and all participants will be followed up until 24 months post-randomisation. The qualitative sub-study will run throughout the trial. One-sided superiority testing will be performed at two stages: in an interim analysis and at the full sample size of 1318 participants, prior to the non-inferiority analysis. The interim superiority analysis is estimated to require 530 participants with complete data – i.e., 664 (332 per arm) participants, assuming 20% attrition. Should superiority be demonstrated at either of these two stages the trial will close. The end of the trial is defined as the last participant's last data item within the 24-month follow-up period. Procedure/Surgery Data sharing statement to be made available at a later date 1837f769-79f1-4422-9875-3395be117186 49b85053-5644-4169-a1fc-736a7e6163e2 f5d9c2c5-2562-4960-92d3-bcda2cde1ed6 a7416ae4-c758-43bf-91c3-0d3083bdfac0 6846bf7a-1002-401c-bb6f-628c6167e093 No Rachel Kelly Public

Clinical Trials Research Unit University of Leeds

Leeds United Kingdom LS2 9JT +44 (0)113 3436912 ROSIER@leeds.ac.uk Public Andrew Smith Principal investigator

Leeds Teaching Hospitals NHS Trust

Leeds United Kingdom LS9 7TF - andrewmsmith@nhs.net Public Giles Toogood Scientific

Leeds Teaching Hospitals NHS Trust

Leeds United Kingdom LS9 7TF - giles.toogood@nhs.net Public University of Leeds University/education https://ror.org/024mrxd33 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 13728688 true COMBAT: Clinical- and cost-effectiveness, safety and acceptability of COMBined phacovitrectomy, versus sequentiAl viTrectomy and cataract surgery, for the management of rhegmatogenous retinal detachment: A Randomised Equivalence Clinical Trial COMBAT Aim To determine whether, in people with non-highly myopic phakic rhegmatogenous retinal detachment (RRD) (Population), phacovitrectomy (Intervention) is equivalent (equivalence margin +/- 7 Early Treatment Diabetic Retinopathy Study ETDRS letters) to vitrectomy and subsequent cataract surgery (phacoemulsification) if/when needed (Comparator) for improving vision following surgery (primary Outcome) but superior for other (secondary) outcomes (as listed in this protocol) in the 52 weeks (+/- 6 weeks) after surgery. Objectives To determine if, in people presenting with non-highly myopic phakic RRD, phacovitrectomy (i.e. removing the cataract and doing vitrectomy to repair the RRD) is as good or better as doing only the retinal detachment repair with vitrectomy and then, if and when the cataract develops, doing a phaco (i.e. cataract surgery) and to assess post-trial implementation strategies and scalability. Background and study aims The retina is the layer at the back of the eye that allows us to see. Sometimes, it can detach from the wall of the eye, causing a condition called rhegmatogenous retinal detachment (RRD), which leads to vision loss and requires surgery. The most common surgery for RRD is vitrectomy, but this can lead to complications like cataracts, which worsen over time and need to be removed with another surgery. Cataract surgery involves replacing the cloudy lens with a clear artificial one. Currently, it's unclear whether it's better to perform both surgeries at the same time or separately. The COMBAT study aims to find out which approach is best by comparing the outcomes of patients who have vitrectomy alone versus those who have both surgeries together. Who can participate? Adults aged 50 and older who have RRD but are not highly myopic (less than -6 diopters or an axial length of 26.5 mm or less) and have not had previous vitreoretinal surgery. Participants must be scheduled for a pars plana vitrectomy to repair their RRD. What does the study involve? Participants will be randomly assigned to one of two groups: one group will have vitrectomy first and, if needed, cataract surgery later; the other group will have both surgeries at the same time. The study will compare their vision, the number of successful retina reattachments, patient satisfaction, complications, and costs. What are the possible benefits and risks of participating? The possible benefits include improved vision and a better understanding of the best surgical approach for RRD. However, there are risks associated with any surgery, including complications from vitrectomy and cataract surgery. Where is the study run from? Queen's University Belfast (UK) When is the study starting and how long is it expected to run for? November 2024 to October 2028. Who is funding the study? Queen's University Belfast (UK) Who is the main contact? Colette Jackson, Trial Manager, colette.jackson@nictu.hscni.net Professor Noemi Lois, Chief Investigator, at n.lois@qub.ac.uk Change in Best-Corrected Visual Acuity (BCVA) in the study eye from baseline to 52 weeks (+/- 6 weeks) after surgery (equivalence margin +/- 7 ETDRS letters). 1. Primary anatomical success is measured using retinal attachment status at 52 weeks (+/- 6 weeks) after one vitrectomy 2. Final anatomical success is measured using retinal attachment status at 52 weeks (+/- 6 weeks) after two or more vitrectomies 3. Intraoperative complications are measured using severity score during surgery 4. Postoperative complications are measured using severity score at 52 weeks (+/- 6 weeks) after surgery 5. Number and type of surgeries performed are measured using surgical records at 52 weeks (+/- 6 weeks) after surgery 6. Refractive error is measured using the difference between aimed and obtained post-operative refraction at 12 weeks after surgery in the phaco-vitrectomy arm and 6-8 weeks post-cataract surgery in the vitrectomy only arm 7. Proportion of participants with BCVA <69 letters is measured using BCVA test at 52 weeks (+/- 6 weeks) after surgery 8. Proportion of participants with BCVA <34 letters is measured using BCVA test at 52 weeks (+/- 6 weeks) after surgery 9. Time to achieve ‘best vision’ is measured using BCVA test at baseline and 52 weeks (+/- 6 weeks) after surgery 10. Change in BCVA from baseline over time is measured using BCVA test at baseline and 52 weeks (+/- 6 weeks) after surgery 11. Health-related quality of life is measured using EuroQol-5 level (EQ-5D-5L) at baseline and 52 weeks (+/- 6 weeks) after surgery 12. Vision-specific quality of life is measured using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) at baseline and 52 weeks (+/- 6 weeks) after surgery 13. Participant’s experience and acceptability of treatments are measured using questionnaires at 52 weeks (+/- 6 weeks) after surgery 14. Use of health and social care services and non-health care is measured using questionnaires at 52 weeks (+/- 6 weeks) after surgery 15. Safety is measured using AE/SAE reporting at 52 weeks (+/- 6 weeks) after surgery Ethics approval required Yorkshire & The Humber - Leeds West Research Ethics Committee

NHSBT Newcastle Blood Donor Centre, Holland Drive

Newcastle-upon-Tyne United Kingdom NE2 4NQ 25/YH/0056 10.1186/ISRCTN13728688 338079 CPMS: 60043 338079 60043 Interventional randomized controlled trial Interventional Randomised controlled trial Treatment 2028-10-31T00:00:00.000Z United Kingdom England Northern Ireland Scotland Belfast Health and Social Care Trust

Trust Headquarters A Floor - Belfast City Hospital Lisburn Road

Belfast Northern Ireland BT9 7AB A3X4A@2.16.840.1.113883.2.1.3.2.4.18.48 Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 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 Guys and St Thomas' NHS Foundation Trust

249 Westminster Bridge Road

London England SE1 7EH Kings College Hospital

Mapother House De Crespigny Park Denmark Hill

London England SE5 8AB NV178@2.16.840.1.113883.2.1.3.2.4.18.48 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 Buckinghamshire Healthcare NHS Trust

Amersham Hospital Whielden Street

Amersham England HP7 0JD RXQ@2.16.840.1.113883.2.1.3.2.4.18.48 County Durham and Darlington NHS Foundation Trust

Darlington Memorial Hospital Hollyhurst Road

Darlington England DL3 6HX RXP@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 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 Moorfields Eye Hospital NHS Foundation Trust

162 City Road

London England EC1V 2PD RP6@2.16.840.1.113883.2.1.3.2.4.18.48 Oxford University Hospitals NHS Foundation Trust

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RTH@2.16.840.1.113883.2.1.3.2.4.18.48 Sandwell and West Birmingham Hospitals NHS Trust

City Hospital Dudley Road

Birmingham England B18 7QH Sheffield Teaching Hospitals NHS Foundation Trust

Northern General Hospital Herries Road

Sheffield England S5 7AU RHQ@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 England TS4 3BW RTR@2.16.840.1.113883.2.1.3.2.4.18.48 South Tyneside and Sunderland NHS Foundation Trust

Sunderland Royal Hospital Kayll Road

Sunderland England SR4 7TP R0B@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 The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTD@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal Wolverhampton NHS Trust

New Cross Hospital Wolverhampton Road Heath Town

Wolverhampton England WV10 0QP University Hospital Southampton NHS Foundation Trust

Southampton General Hospital Tremona Road

Southampton England SO16 6YD RHM@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Bristol and Weston NHS Foundation Trust

Trust Headquarters Marlborough Street

Bristol England BS1 3NU RA7@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals of Leicester NHS Trust

Leicester Royal Infirmary Infirmary Square

Leicester England LE1 5WW RWE@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Sussex NHS Foundation Trust

Worthing Hospital Lyndhurst Road

Worthing England BN11 2DH RYR@2.16.840.1.113883.2.1.3.2.4.18.48 York and Scarborough Teaching Hospitals NHS Foundation Trust

York Hospital Wigginton Road

York England YO31 8HE RCB@2.16.840.1.113883.2.1.3.2.4.18.48 Mid and South Essex NHS Foundation Trust

Prittlewell Chase

Westcliff-on-sea England SS0 0RY RAJ@2.16.840.1.113883.2.1.3.2.4.18.48 NHS Greater Glasgow and Clyde

J B Russell House Gartnavel Royal Hospital 1055 Great Western Road Glasgow

Glasgow Scotland G12 0XH SG999@2.16.840.1.113883.2.1.3.8.2.16.1 Queen's University Belfast

Centre for Public Health

Belfast Northern Ireland BT7 1NN Royal Berkshire NHS Foundation Trust

Royal Berkshire Hospital London Road

Reading England RG1 5AN RHW@2.16.840.1.113883.2.1.3.2.4.18.48 Wirral University Teaching Hospital NHS Foundation Trust

Arrowe Park Hospital Arrowe Park Road Upton

Wirral England CH49 5PE RBL@2.16.840.1.113883.2.1.3.2.4.18.48 Nottingham University Hospitals NHS Trust - Queen's Medical Centre Campus

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH RX1RA@2.16.840.1.113883.2.1.3.2.4.18.48 Imperial College NHS Trust - Western Eye Hospital

Western Eye Hospital, Marylebone Road

London England NW1 5QH NHS Lothian - Princess Alexandra Eye Pavilion

Princess Alexandra Eye Pavilion, Chalmers Street

Edinburgh Scotland EH3 9HA Patient 1. Adults ≥50 years of age 2. Non-highly myopic (< -6 diopters; ≤26.5 mm axial length) phakic RRD 3. Naïve to previous vitreoretinal surgery 4. Pars plana vitrectomy is planned to repair their RRD Mixed 50 Years 150 Years All 276 0 1. Presence of a “formed/established cataract.” A “formed/established cataract” is defined as a cataract that, based on the Age-Related Eye Disease Study (AREDS) Research Group, is graded as nuclear sclerosis of >3 and/or if there is an anterior cortical cataract and/or a subcapsular posterior cataract involving the visual axis. 2. Pseudophakia or aphakia. 3. High myopia (≥ -6 diopters; >26.5 mm axial length). 4. Giant retinal tear (i.e. presence of one or more retinal tears of >3 clock hours in size) 5. Retinal dialysis 6. Inclusion in an investigational drug study 7. Declined consent for participation 2025-05-09T00:00:00.000Z 2027-04-30T00:00:00.000Z Rhegmatogenous retinal detachment Eye Diseases Following consent, participants will be reviewed by the research team, including their surgeon. Previous medical and eye history will be reviewed, and measurements of the eye and baseline data (including 5 questionnaires) will then be collected. Patients will then be seen again at 1, 6, 12, and 52 weeks (+/- 6 weeks) post-surgery for the measurements and baseline data collection. Participation in the study will end following the 52-week visit. Participants will also have the option at their initial study discussion to give consent to be contacted in the future to take part in individual interviews to talk about their opinions and experiences of treatment. The study PPI group gave favorable feedback about the proposed options for the consenting process (written/verbal) for interviews. Participants can receive an audio recording of their consent if they request this. A total of 3 (maximum) individual interviews will be undertaken by the participant. Health care professionals will also be invited to give online consent to take part in an individual/small group discussion to share their views on the barriers and facilitators involved in the implementation of the COMBAT study. Studies within a Trial (SWAT) There will be 2 SWATs embedded in the trial: SWAT A - Will record the proportion in each of the demographic groups who are recruited and retained at each site. We will also collect information over the course of the trial on how often the translated PIL are used and whether people for whom these are used are recruited and retained. SWAT B - Sites who are willing to take part will evaluate whether an EDI-informed PIL increases the recruitment of underserved groups compared to the standard PIL. The exact content of the modified PIL is dependent on qualitative, diverse PPI work to be done during (around) the first year of the COMBAT study. Timeline The total study duration will be 48 months: Months 1-6: Set up activities. Months 7-15: Pilot Phase - Opening site, recruitment, data collection & follow-up, qualitative small discussions/interviews tasks. Months 16-30: Main Study - Opening site, recruitment, data collection & follow-up, qualitative small discussions/interviews tasks. Months 31-42: Follow-up, data cleaning, qualitative small discussions/interviews tasks. Months 43-48: Write-up, reporting, and dissemination. Procedure/Surgery Following publication of the primary and secondary outcomes and after data has been fully exploited by the COMBAT research team, there may be scope to conduct additional analyses on the data collected. In such instances, formal requests for data will need to be made in writing to the CI via the NICTU. If there are requests for data sharing, these will be reviewed on a case-by-case basis by the CI and NICTU (Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast) with approval by the Sponsor required before data are shared. Available on request 2e924817-0bd5-4186-bfd9-f997d8f699a4 bfbe0c4f-464c-4f81-adf3-077013fe4e1f 4776bcc0-3343-440e-a55b-3f4ab3b26269 f038fbb2-cfde-4ce1-a1e9-4ed96f81653a Yes Colette Jackson https://orcid.org/0000-0001-7814-0749 Public

Northern Ireland Clinical Trials Unit 7 Lennoxvale

Belfast United Kingdom BT9 5BY - colette.jackson@nictu.hscni.net Public Noemi Lois https://orcid.org/0000-0003-2666-2937 Scientific Principal investigator

The Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road

Belfast United Kingdom BT9 7BL - n.lois@qub.ac.uk Public Queen's University Belfast University/education https://ror.org/00hswnk62 Non-commercial Queen's University Belfast http://dx.doi.org/10.13039/501100000873 30482473 true A Phase II, two-part study to assess the safety, antiviral biomarker responses, and efficacy of inhaled SNG001 for the treatment of patients with a confirmed respiratory virus infection undergoing invasive mechanical ventilation The primary objective of Part 1 will be to evaluate the safety of SNG001 administration to participants with a confirmed respiratory virus infection undergoing IMV. The primary objective of Part 2 will be to evaluate the efficacy of SNG001, versus placebo, in participants with a confirmed respiratory virus infection undergoing IMV. Secondary objectives of part 2: 1. To evaluate the safety of SNG001 administration to participants with a confirmed respiratory virus infection undergoing IMV. 2. To evaluate antiviral and biomarker responses after administration of SNG001. Background and study aims The purpose of this study is to assess if the medicine (SNG001) could potentially be a treatment for patients who have severe viral lung infections (‘pneumonia’) such as those caused by flu or COVID-19. SNG001 contains interferon-β, a protein that occurs naturally in humans, which helps the body’s immune system fight off viruses. Clinical trials have shown that SNG001 has anti-viral activity and potential beneficial effects on clinical outcomes in patients with viral infections in the lung. In critically ill patients who require mechanical ventilation due to severe viral pneumonia, SNG001 could help clear the infection and thereby improve outcomes and recovery. SNG001 is delivered by inhalation using a nebuliser to target the virus in the lungs. SNG001 has been extensively evaluated in other patient groups including those with COVID-19, COPD and asthma. Who can participate? Patients who require mechanical ventilation due to a virus infection in the lung What does the study involve? This study has two parts. Part 1 will assess the safety of SNG001. A small group of participants will receive a low dose. Based on recommendations from an independent safety committee, a second group may receive a higher dose. The dose for Part 2 will be determined by the results from Part 1. Part 2 will evaluate how effective SNG001 is compared to placebo in up to 450 Participants who will be randomly allocated to receive either SNG001 or placebo. They will be dosed for 14 days or until hospital discharge whichever happens first. During the study participants will still receive standard of care including other treatments for viral pneumonia What are the possible benefits and risks of participating? The potential health benefit from participating in this study is that SNG001 may help patients recover from their lung infection, shorten their symptoms and/or shorten the length of time they will need to be on a ventilator. In addition, the results of this study will be used for future product development decisions to improve SNG001. Information learned from the study may help other people in the future. SNG001 has been investigated in seven completed clinical studies, across various populations including asthmatics, COPD and COVID-19 patients. Of the 758 patients treated with SNG001, 342 patients with COVID-19 required hospitalisation and oxygen supplementation due to the severity of their disease. Treatment with SNG001 across the different studies was generally well tolerated, with no specific safety signals being observed, whether related to local tolerance or systemic effects. SNG001 has not been administered to patients with severe viral lung infections undergoing IMV hence the specific focus of Part 1 of the study on safety. A review of the safety data and potential risks supports the design of the proposed clinical trial (SG021) of SNG001. To minimize any potential risks Part 1 of the study will initially assess safety in patients receiving a lower dose of SNG001. The independent data review committee will provide ongoing oversight of safety throughout both parts of the study. Where is the study run from? Synairgen Research Ltd (UK) When is the study starting and how long is it expected to run for? November 2024 to March 2027 Who is funding the study? Synairgen Research Ltd (UK) Who is the main contact? Sophie Hemmings, submissions@synairgen.com Part 1: The occurrence and severity of adverse events (AEs) and serious adverse events (SAEs), including prespecified respiratory and cardiovascular deteriorations, assessed by site staff using recognised assessment tools and/or patients’ clinical condition, up to 28 days from randomisation Part 2: All-cause mortality within 28 days from randomisation measured using the proportion of patients who died between randomisation and day 28 in each study arm Current secondary outcomes as of 07/07/2026; Part 1: None Part 2: 1. The occurrence and severity of AEs and SAEs, including pre-specified respiratory and cardiovascular deteriorations, assessed by site staff using recognised assessment tools and/or patients’ clinical condition, up to Day 42 2. Organ failure assessed using the modified Sequential Organ Failure Assessment (mSOFA) score (5-point scores for the different organ systems) daily during ICU stay up to day 15 3. Time to extubation, defined as the date free from all tubes (endotracheal tube and tracheostomy tube), which was sustained for a minimum of 48 hours, up to 28 days from randomisation 4. Ventilator-free days over 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were not receiving mechanical ventilation 5. Duration of ICU stay up to 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were staying in the ICU 6. Duration of hospital stay up to 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were staying in the hospital 7. All-cause mortality within 28 days post final dose 8. Alive and free of organ support at 28 days from randomisation and at 28 days post final dose 9. Clinical improvement assessed using the Ordinal Scale for Clinical Improvement (OSCI) score (8-point scale) from baseline to 7, 10, 14 and 28 days post-randomisation 10. Time to first negative virus test in tracheal aspirates assessed daily up to Day 7 by reverse transcription polymerase chain reaction (RT-PCR) test 11. Levels of IFNβ-dependent biomarkers in tracheal aspirates measured using PCR daily up to Day 7 Previous secondary outcomes: Part 1: None Part 2: 1. The occurrence and severity of AEs and SAEs, including pre-specified respiratory and cardiovascular deteriorations, assessed by site staff using recognised assessment tools and/or patients’ clinical condition, up to Day 42 2. Organ failure assessed using the modified Sequential Organ Failure Assessment (mSOFA) score (5-point scores for the different organ systems) daily during ICU stay up to day 15 3. Time to extubation, defined as the date free from all tubes (endotracheal tube and tracheostomy tube), which was sustained for a minimum of 48 hours, up to 28 days from randomisation 4. Ventilator-free days over 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were not receiving mechanical ventilation 5. Duration of ICU stay up to 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were staying in the ICU 6. Duration of hospital stay up to 28 days from randomisation measured using the mean number of days between randomisation and day 28 in each study arm when patients were staying in the hospital 7. Clinical improvement assessed using the Ordinal Scale for Clinical Improvement (OSCI) score (8-point scale) from baseline to 7, 10, 14 and 28 days post-randomisation 8. Time to first negative virus test in tracheal aspirates assessed daily up to Day 7 by reverse transcription polymerase chain reaction (RT-PCR) test 9. Levels of IFNβ-dependent biomarkers in tracheal aspirates measured using PCR daily up to Day 7 Ethics approval required South Central - Hampshire B REC

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/SC/0385 10.1186/ISRCTN30482473 1010122 CPMS: 62305, SG021 1010122 62305 SG021 Double-blind randomized placebo-controlled parallel-group trial (Part 1 of the study is open-label, uncontrolled, to assess the safety of SNG001) Interventional Randomised controlled trial Efficacy Safety Treatment 2026-03-13T00:00:00.000Z United Kingdom England Scotland Wales Belgium France Netherlands Spain United States of America Aberdeen Royal Infirmary

Foresterhill Road

Aberdeen Scotland AB25 2ZN N101H@2.16.840.1.113883.2.1.3.8.2.16.2 University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital Mindelsohn Way Edgbaston

Birmingham England B15 2GW RRK@2.16.840.1.113883.2.1.3.2.4.18.48 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 Royal Sussex County Hospital

Eastern Road

Brighton England BN2 5BE RX2N2@2.16.840.1.113883.2.1.3.2.4.18.48 Cardiff and Vale U H B

St. Davids Hospital Cowbridge Road East

Cardiff Wales CF11 9XB V11409@2.16.840.1.113883.2.1.3.2.4.18.48 Glasgow Royal Infirmary

84 Castle Street

Glasgow Scotland G4 0SF G107H@2.16.840.1.113883.2.1.3.8.2.16.2 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 Leicester Royal Infirmary

Infirmary Square

Leicester England LE1 5WW RFR0H@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Free London NHS Foundation Trust

Royal Free Hospital Pond Street

London England NW3 2QG RAL@2.16.840.1.113883.2.1.3.2.4.18.48 St George's Healthcare Nhst

Blackshaw Road

London England SW17 0QT RAX63@2.16.840.1.113883.2.1.3.2.4.18.48 The James Cook University Hospital

Marton Road

Middlesbrough England TS4 3BW RTRAT@2.16.840.1.113883.2.1.3.2.4.18.48 The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTD@2.16.840.1.113883.2.1.3.2.4.18.48 Southampton General Hospital Laboratory

Southampton General Hospital Tremona Road

Southampton England SO16 6YD 694X0@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 The Royal Victoria Infirmary

Queen Victoria Road

Newcastle upon Tyne England NE1 4LP RTD02@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 07/07/2026: 1. Informed consent or legal representative’s consent obtained 2. Patients ≥35 (UK only) to 50 years of age at the time of consent 3. Patient admitted to the ICU and requiring IMV due to a respiratory virus infection* 4. Presence of Influenza A (Flu A), Influenza B (Flu B), respiratory syncytial virus (RSV), rhinovirus (RV), adenovirus, parainfluenza, human metapneumovirus (HMPV), or coronaviruses (including SARS COV 2 and seasonal coronaviruses) in an LRT sample, confirmed by a positive virus test using a Sponsor approved rapid POC test (e.g., reverse transcription polymerase chain reaction [RT-PCR]), with a reported cycle threshold (Ct) value that meets the criteria as specified for each virus in Appendix A** 5. Time from intubation to administration of first dose of study medication ≤48 hours 6. Women of childbearing potential must have a negative pregnancy test. For this study, women of childbearing potential are defined as women <55 years old Part 2: 1.1. Patients ≥18 and <50 years of age at the time of consent, with an immunocompromising condition, including: 1.1.1. Haematological malignancy; 1.1.2. Bone marrow transplantation; or 1.1.3. Immunosuppressive therapy, including cancer chemotherapy, immune-cell depleting therapy, immunosuppressive therapy for autoimmune disorders, medications for prevention of organ transplantation rejection, or the administration of corticosteroids >20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomisation or 1.2. Patients ≥50 years of age at the time of consent, with or without an immunocompromising condition 2. Patient admitted to the ICU and requiring IMV due to a respiratory virus infection* 3. Presence of Flu A, Flu B, RSV, RV, adenovirus, parainfluenza, HMPV, or coronaviruses (including SARS-COV-2 and seasonal coronaviruses) in an LRT sample, confirmed by a positive virus test using a Sponsor approved rapid POC test (e.g., RT PCR), with a reported Ct value that meets the criteria as specified for each virus in Appendix A** 4. Time from intubation to administration of first dose of study medication ≤48 hours 5. Informed consent or legal representative’s consent obtained 6. Women of childbearing potential must have a negative pregnancy test. For this study, women of childbearing potential are defined as women <55 years old Previous inclusion criteria: Part 1: 1. Informed consent or legal representative’s consent obtained 2. Patients ≥50 years of age at the time of consent 3. Patient admitted to the ICU and requiring IMV due to a respiratory virus infection* 4. Presence of Influenza A (Flu A), Influenza B (Flu B), respiratory syncytial virus (RSV), rhinovirus (RV), adenovirus, parainfluenza, human metapneumovirus (HMPV), or coronaviruses (including SARS COV 2 and seasonal coronaviruses) in an LRT sample, confirmed by a positive virus test using a Sponsor approved rapid POC test (e.g., reverse transcription polymerase chain reaction [RT-PCR]), with a reported cycle threshold (Ct) value that meets the criteria as specified for each virus in Appendix A** 5. Time from intubation to administration of first dose of study medication ≤48 hours 6. Women of childbearing potential must have a negative pregnancy test. For this study, women of childbearing potential are defined as women <55 years old Part 2: 1.1. Patients ≥18 and <50 years of age at the time of consent, with an immunocompromising condition, including: 1.1.1. Haematological malignancy; 1.1.2. Bone marrow transplantation; or 1.1.3. Immunosuppressive therapy, including cancer chemotherapy, immune-cell depleting therapy, immunosuppressive therapy for autoimmune disorders, medications for prevention of organ transplantation rejection, or the administration of corticosteroids >20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomisation or 1.2. Patients ≥50 years of age at the time of consent, with or without an immunocompromising condition 2. Patient admitted to the ICU and requiring IMV due to a respiratory virus infection* 3. Presence of Flu A, Flu B, RSV, RV, adenovirus, parainfluenza, HMPV, or coronaviruses (including SARS-COV-2 and seasonal coronaviruses) in an LRT sample, confirmed by a positive virus test using a Sponsor approved rapid POC test (e.g., RT PCR), with a reported Ct value that meets the criteria as specified for each virus in Appendix A** 4. Time from intubation to administration of first dose of study medication ≤48 hours 5. Informed consent or legal representative’s consent obtained 6. Women of childbearing potential must have a negative pregnancy test. For this study, women of childbearing potential are defined as women <55 years old Mixed 18 Years 100 Years All 450 11 Current exclusion criteria as of 07/07/2026: Part 1: 1. Expected termination of IMV within 24 hours from the time of randomisation 2. Life expectancy <24 hours 3. Liver failure (Child-Pugh C) 4. Severe congestive heart failure (New York Heart Association [NYHA] IV) 5. Receipt of lung transplant 6. Known or suspected active tuberculosis, or infection with other mycobacteria 7. Known or suspected systemic fungal infection 8. Anticipated transfer to another hospital 9. Current need for long-term mechanical ventilation 10. Use of inhaled sedation 11. Presence of tracheostomy or laryngectomy 12. Requirement for airway pressure release ventilation mode 13. History of hypersensitivity to natural or recombinant IFNβ or to any of the excipients in the drug preparation 14. Any condition, including findings in the patient’s medical history or in the pre-randomisation study assessments that in the opinion of the Investigator, constitute a risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation. 15. Participation in previous clinical studies of SNG001 16. Current or previous participation in another clinical study where the participant has received a dose of an Investigational Medicinal Product (IMP) containing small molecules within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or containing biologicals within 3 months prior to entry into this study 17. Known or suspected pregnancy 18. Females who are breastfeeding or lactating 19. Immunocompromising condition, including: 19.1. Established acquired immune deficiency syndrome (AIDS) defined as a cluster of differentiation 4 (CD4) count <200 cells/microL, and/or the presence of any AIDS-defining condition; 19.2. Haematological malignancy; 19.3. Bone marrow transplantation; or 19.4. Immunosuppressive therapy including cancer chemotherapy, immune-cell depleting therapy, immunosuppressive therapy for autoimmune disorders, medications for prevention of organ transplantation rejection, or the administration of corticosteroids >20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomisation 20. Severe chronic lung disease requiring home oxygen therapy, including chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis Part 2: 1. Expected termination of IMV within 24 hours from the time of randomisation 2. Life expectancy <24 hours 3. Liver failure (Child-Pugh C) 4. Severe congestive heart failure (NYHA IV) 5. Receipt of lung transplant 6. Known or suspected active tuberculosis, or infection with other mycobacteria 7. Known or suspected active systemic fungal infection 8. Immunocompromising condition, including: 8.1. Haematological malignancy requiring induction or consolidation therapy within 3 months prior to randomisation 8.2. Bone marrow transplant within 6 months prior to randomisation 8.3. Solid organ transplant within 6 months prior to randomisation 8.4. Corticosteroids >75 mg of prednisone or equivalent per day, administered continuously for >7 days prior to randomisation 8.5. Methotrexate therapy at randomisation, if the indication is chemotherapy for cancer 8.6. Chimeric antigen receptor (CAR)-T cell therapy, administered within 3 months prior to randomisation 8.7. Ibrutinib or alemtuzumab, administered within 3 months prior to randomisation 8.8. Neutropenia <500/mm3 not due to sepsis 8.9. Clinical presentation consistent with severe bone marrow suppression or pancytopenia 8.10. Established AIDS, defined as a CD4 count <200 cells/microL, and/or the presence of any AIDS-defining condition 9. Anticipated transfer to another hospital, which would prevent the participant from continuing in the study and completing protocol assessments. 10. Need for long-term mechanical ventilation prior to ICU admission. 11. Use of inhaled sedation. 12. Presence of tracheostomy or laryngectomy. 13. History of hypersensitivity to natural or recombinant IFNβ or to any of the excipients in the drug preparation. 14. Any condition, including findings in the patient’s medical history or in the pre-randomisation study assessments that in the opinion of the Investigator, constitute a risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation. 15. Participation in previous clinical studies of SNG001. 16. Current or previous participation in another clinical study where the participant has received a dose of an IMP containing small molecules within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or containing biologicals within 3 months prior to entry into this study. 17. Known or suspected pregnancy. 18. Females who are breastfeeding or lactating. 19. Severe chronic lung disease requiring home oxygen therapy, including chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis Previous exclusion criteria: Part 1: 1. Expected termination of IMV within 24 hours from the time of randomisation 2. Life expectancy <24 hours 3. Liver failure (Child-Pugh C) 4. Severe congestive heart failure (New York Heart Association [NYHA] IV) 5. Receipt of lung transplant 6. Known or suspected active tuberculosis, or infection with other mycobacteria 7. Known or suspected systemic fungal infection 8. Anticipated transfer to another hospital 9. Current need for long-term mechanical ventilation 10. Use of inhaled sedation 11. Requirement for airway pressure release ventilation mode 12. History of hypersensitivity to natural or recombinant IFNβ or to any of the excipients in the drug preparation 13. Any condition, including findings in the patient’s medical history or in the pre-randomisation study assessments that in the opinion of the Investigator, constitute a risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation. 14. Participation in previous clinical studies of SNG001 15. Current or previous participation in another clinical study where the participant has received a dose of an Investigational Medicinal Product (IMP) containing small molecules within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or containing biologicals within 3 months prior to entry into this study 16. Known or suspected pregnancy 17. Females who are breastfeeding or lactating 18. Immunocompromising condition, including: 18.1. Established acquired immune deficiency syndrome (AIDS) defined as a cluster of differentiation 4 (CD4) count <200 cells/microL, and/or the presence of any AIDS-defining condition; 18.2. Haematological malignancy; 18.3. Bone marrow transplantation; or 18.4. Immunosuppressive therapy including cancer chemotherapy, immune-cell depleting therapy, immunosuppressive therapy for autoimmune disorders, medications for prevention of organ transplantation rejection, or the administration of corticosteroids >20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomisation 19. Severe chronic lung disease requiring home oxygen therapy, including chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis Part 2: 1. Expected termination of IMV within 24 hours from the time of randomisation 2. Life expectancy <24 hours 3. Liver failure (Child-Pugh C) 4. Severe congestive heart failure (NYHA IV) 5. Receipt of lung transplant 6. Known or suspected active tuberculosis, or infection with other mycobacteria 7. Known or suspected systemic fungal infection 8. Established AIDS, defined as a CD4 count <200 cells/microL, and/or the presence of any AIDS-defining condition 9. Anticipated transfer to another hospital 10. Current need for long-term mechanical ventilation 11. Use of inhaled sedation 12. History of hypersensitivity to natural or recombinant IFNβ or to any of the excipients in the drug preparation 13. Any condition, including findings in the patient’s medical history or in the pre-randomisation study assessments that in the opinion of the Investigator, constitute a risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation 14. Participation in previous clinical studies of SNG001 15. Current or previous participation in another clinical study where the participant has received a dose of an IMP containing small molecules within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or containing biologicals within 3 months prior to entry into this study 16. Known or suspected pregnancy 17. Females who are breastfeeding or lactating 2025-12-04T00:00:00.000Z 2026-02-02T00:00:00.000Z Respiratory viral infections Infections and Infestations Current interventions as of 07/07/2026: Part 1 (Randomized; double-blind; placebo-controlled): Participants who meet study entry criteria will receive the following intervention: Experimental Arm: Cohort 1, SNG001 (0.65 ml of nebuliser solution containing 12 MIU/ml of IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge, whichever occurs earlier, in addition to Standard of Care (SOC). Cohort 1, Placebo Comparator Arm: Placebo to match the experimental arm of nebuliser solution (identical to the experimental arm but without IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Cohort 2 (Optional), SNG001 (two syringes) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Cohort 2 (Optional), Placebo Comparator Arm: Placebo to match the experimental arm of nebuliser solution (identical to the experimental arm but without IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Part 2 (Randomized; double-blind; placebo-controlled): Participants who meet study entry criteria will be randomised (using an online tool) to receive either of the following interventions: Experimental Arm: SNG001 (two syringes) of nebuliser solution containing 12 MIU/ml of IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Placebo Comparator Arm: SNG001 placebo (two syringes) of nebuliser solution identical to the experimental arm but without IFNβ-1a given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge, whichever occurs earlier, in addition to SOC. Previous interventions: Part 1 (Open-label; non-comparative): Participants who meet study entry criteria will receive the following intervention: Experimental Arm: Cohort 1, SNG001 (0.65 ml of nebuliser solution containing 12 MIU/ml of IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to Standard of Care (SOC). Cohort 2 (Optional), SNG001 (at a dose recommended by the IDMC) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Part 2 (Randomized; double-blind; placebo-controlled): Participants who meet study entry criteria will be randomised (using an online tool) to receive either of the following interventions: Experimental Arm: SNG001 (at a dose recommended by the IDMC, (based on results of Part 1) of nebuliser solution containing 12 MIU/ml of IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Placebo Comparator Arm: SNG001 placebo to match experimental arm (based on results of Part 1) of nebuliser solution identical to the experimental arm but without IFNβ-1a) given by inhalation using a nebuliser, once a day for a maximum of 14 days or until hospital discharge whichever occurs earlier, in addition to SOC. Drug Phase II Interferon beta-1a (IFN-β1a)/Aerogen Clinical Controller System Not expected to be made available Results Basic results see attached file ISRCTN30482473_BasicResults_07Jul2026.pdf (added 07/07/2026)

b7d52db8-874a-47ac-85a2-27812ace04b9 6e1189bb-bbbf-4dd5-8b10-6ee94b11608f 0dfcb0ad-a26d-45a4-a349-ad284e25a20e 4b0ccfdb-9cc4-4ed2-8300-473d7f5bb800 No Basic results ISRCTN30482473_BasicResults_07Jul2026.pdf 79a6f18c-5b65-41ba-b01c-25b0dba659e9 true application/pdf 187001 2df82d8fab64dd88139d2bd7ef65aa21 Sophie Hemmings Scientific

Tremona Road

Southampton United Kingdom SO16 6YD +44 (0)23 80512 800 submissions@synairgen.com Public Ahilanandan Dushianthan Principal investigator

Tremona Road

Southampton United Kingdom SO16 6YD +44 (0)2380512800 submissions@synairgen.com Public Synairgen (United Kingdom) Industry https://ror.org/04h6ep125 Commercial Synairgen Research Ltd