39415632 true Vagus Nerve Stimulation for epilepsy in children and adults: Assessment of Longer term clinical and cost Effectiveness in a Randomised controlled Trial VNS-ALERT Primary objective: To determine the clinical effectiveness of VNS versus no VNS at 6 months in people, with or without intellectual disability, aged 5 years and over with treatment refractory epilepsy Secondary objectives: 1. To determine the clinical effectiveness of VNS versus no VNS at 12 months in people, with or without intellectual disability, aged 5 years and over with treatment refractory epilepsy 2. To determine the clinical effectiveness of VNS versus no VNS at 6 and 12 months in people with intellectual disability, aged 5 years and over with treatment refractory epilepsy 3. To determine the longer-term clinical effectiveness (beyond 2 years) of VNS 4. To determine whether the clinical effectiveness of VNS changes over time during longer term follow-up 5. To determine the effectiveness of VNS or no-VNS on patient and caregiver quality of life Background and study aims Over 600,000 people in the UK have epilepsy. For a third, medication is ineffective, referred to as refractory epilepsy, or ‘drug-resistant epilepsy’, which can severely impact quality of life and reduce life expectancy. Brain surgery can help some with drug-resistant epilepsy by removing the problematic brain area, but identifying this area is not always possible, and surgery is only effective for 50-60% in the long term. Another possible treatment is vagus nerve stimulation (VNS). This involves implanting a battery under the skin on the upper chest (like a pacemaker) and connecting it to the vagus nerve in the neck. Although VNS is approved for drug-resistant epilepsy, its long-term effectiveness and who it works for is not known. For example, we do not know how well it works for children or adults with epilepsy and intellectual disabilities, who make up half of NHS VNS recipients. Our project aims to find out if VNS provides both short- and long-term benefits for people with drug-resistant epilepsy, including those with intellectual disabilities. Who can participate? We will recruit 300 participants from epilepsy surgery centres over four years, following them for a minimum of an additional two years. Participants will be over 5 years old with drug-resistant epilepsy unsuitable for, or which has failed, brain surgery. Around half will have intellectual disability. What does the study involve? Persons identified as suitable for VNS by a multi-disciplinary team will be invited. Those agreeing will be randomised: 150 to immediate VNS activation, 75 to activation after 6 months, and 75 to activation after 12 months. What are the possible benefits and risks of participating? Benefits: The research might help other people with epilepsy in the future. Risks: Participants might have to wait a little while before their device is switched on. - Keeping track of seizures and answering questions takes time. - VNS can have some side effects such as a hoarse or croaky voice. Where is the study run from? The trial Sponsor is University of Liverpool and is being run by the Liverpool Clinical Trials Centre at the University of Liverpool (UK). When is the study starting and how long is it expected to run for? May 2026 to May 2032 Who is funding the study? The trial is being funded by the NIHR Health Technology Assessment Programme (UK). Who is the main contact? The Chief Investigator is Professor Tony Marson The Trial Manager at the LCTC is Stephanie Willshaw vnstrial@liverpool.ac.uk ‘Seizure free days’ at 6 months Seizure diary (minimum of 1 month diary completion prior to timepoint) VNS Implantation, 6 months ‘Seizure free days’ at 12 months Seizure diary (minimum of 1 month diary completion prior to timepoint) VNS Implantation, 12months ‘Seizure free days’ Seizure diary (minimum of 1 month diary completion prior to timepoint) VNS Implantation, 6, 12, 18, 24 months, then 6-monthly follow-ups to end of trial Seizure frequency Seizure diary (minimum of 1 month diary completion prior to timepoint) VNS Implantation, 3m (post VNS activation), 6, 12, 18, 24 months, then 6-monthly follow-ups to end of trial Seizure severity Liverpool Seizure Severity Scale Randomisation, 6, 12, 18, 24 months, then 12-monthly follow-ups to end of trial Episodes of seizure requiring rescue medication, emergency department attendance or hospital admission Site report, PLICS Continuously throughout the study Mortality Site report Continuously throughout the study Symptoms of depression, anxiety, and anger PROMIS short (anxiety, depression, and anger) Randomisation, 6, 12, 18, 24 months, then 12-monthly follow-ups to end of trial Quality of life of person with epilepsy QoLCE / QoLIE / ELDQoL Randomisation, 6, 12, 18, 24 months, then 12-monthly follow-ups to end of trial Caregiver burden CarerQoL-7D Randomisation, 6, 12, 18, 24 months, then 12-monthly follow-ups to end of trial 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 26/YH/0012 10.1186/ISRCTN39415632 346186 CPMS: 63394, NIHR: 167183 346186 63394 167183 Interventional Randomized controlled trial Open (masking not used) Active Single Treatment Not applicable 2032-05-31T00:00:00.000Z United Kingdom England Scotland Wales The Walton Centre NHS Foundation Trust

Lower Lane Fazakerley

Liverpool England L9 7LJ RET20@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 Lothian

Waverleygate 2-4 Waterloo PLACE Edinburgh

City of Edinburgh Scotland EH1 3EG SS9@2.16.840.1.113883.2.1.3.2.4.18.48 Great Ormond Street Hospital for Children NHS Foundation Trust

Great Ormond Street

London England WC1N 3JH RP4@2.16.840.1.113883.2.1.3.2.4.18.48 Greater Glasgow and Clyde

Gartnavel Royal Hospital 1055 Great Western Road

Glasgow Scotland G12 0XH SG9@2.16.840.1.113883.2.1.3.2.4.18.48 Northern Care Alliance NHS Foundation Trust

Salford Royal Stott Lane

Salford England M6 8HD RM3@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 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 Cardiff & Vale University Lhb

Woodland House Maes-y-coed Road

Cardiff Wales CF14 4HH 7A4@2.16.840.1.113883.2.1.3.2.4.18.48 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 false 1. Aged greater than or equal to 5 years 2. Has treatment refractory focal, generalised, or unclassified epilepsy 3. Epilepsy surgery MDT agrees that VNS should be offered as a treatment for epilepsy 4. Patient (and/or carer) has a good enough understanding of the English language to read and understand study documents Mixed 5 Years 120 Years All 300 0 1. Previous VNS 2. Contraindication to VNS 2026-05-01T00:00:00.000Z 2030-05-01T00:00:00.000Z Epilepsy Nervous System Diseases Patients will be recruited in hospital a minimum of one month prior to their VNS implantation surgery to allow for initial seizure diary completion. To understand how effective VNS is, participants will be randomised to one of the following groups: 1. Immediate VNS activation 2. VNS activation after 6 months 3. VNS activation after 12 months Each delayed activation arm will be compared to the standard care immediate activation arm, with the null hypothesis that there is no difference in outcome between the treatments. A total of 150 participants will be allocated to immediate activation, with 75 participants allocated to each delayed activation arm. All participants in the trial will receive the best available standard care for any long-term symptoms they develop. A randomised controlled trial design has been chosen as it is the most reliable way to assess the effects of treatment. The design is pragmatic in order to allow treatment to be administered based on clinical need. The trial is not blinded as it is not feasible to blind site staff or patients to VNS device activation. Participants will mainly be recruited as part of standard epilepsy multi-disciplinary team MDT meetings where VNS implantation is discussed. Layered and proportionate participant information will be provided to allow an informed decision on participation. Once consent is obtained, demographic information and medical history will be collected, and participants will be provided with a seizure diary to collect seizure free days and seizure frequency for a minimum of one month prior to their VNS device implantation surgery. A randomisation visit will be arranged between 2 weeks and 24 hours prior to the participant’s VNS device implantation surgery. At this visit, details on anti-seizure medications will be collected and participants will complete questionnaires regarding their epilepsy, quality of life, and resource use. The site will randomise the participant to a trial arm, and participants will be informed of their allocation at the visit. The initially completed seizure diary will be returned to the site team for upload at the VNS implantation surgery. Sites will provide a new blank seizure diary to participants at every visit for return at the subsequent visit. Follow-up visits will align with standard care clinic visits every 6 months following VNS device implantation surgery. Participants will be followed for a minimum of 24 months, with follow-up continuing up to 24 months following the final randomised participant. Completed seizure diaries will be returned at each follow-up visit. Questionnaires will be completed at each follow-up up to 24 months, and then annually thereafter. Optional trial items include collection of a blood sample and a copy of a recent EEG to be transferred to a central repository for future research. In addition, informal carers will be asked whether they would like to consent to answering additional questions about their caring experience in line with the timepoints for the person with epilepsy. There is a nested qualitative sub-study that will be explained at the initial MDT screening. Patients may consent to be contacted by the qualitative research team irrespective of participation in the main trial. The qualitative team will separately consent patients and or their carers to complete interviews to explore experiences of VNS-ALERT and VNS devices more broadly. This will improve understanding of trial recruitment, as well as barriers and opportunities for improving information provision about VNS. Public and Patient Involvement PPI groups have been extensively involved in the trial design. This input guided the development of the three arm design, allowing all participants to have a VNS device fitted and to continue in the trial if their device is activated outside their allocated trial arm. The dedicated PPI team has also contributed to the development of study materials, including the patient information leaflet, video, and seizure diary. The Independent Data and Safety Monitoring Committee will meet regularly to review preliminary data and make recommendations about trial progress. The results from this study have the potential to change standard care for people with treatment resistant epilepsy. Device Not Applicable Vagus nerve stimulation Data sharing statement to be made available at a later date 87a5b7b0-a7ac-4a98-80f1-9147a87de1c1 42873b0b-ee90-4872-97ae-45bceeec463f 45aed63e-d5a2-4a99-9e07-85344ea9e773 No Stephanie Willshaw Public Scientific Principal investigator

Liverpool Clinical Trials Centre, The University of Liverpool, Block C Waterhouse Building, 3 Brownlow Street

Liverpool United Kingdom L69 3GL +44 151 794 9766 vnstrial@liverpool.ac.uk Public University of Liverpool University/education Non-commercial NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) 16864220 true The clinical and cost effectiveness of quetiapine for people with borderline personality disorder: A pragmatic, double-blind, placebo-controlled, randomised trial QUEST Primary objective: To test whether adding quetiapine to treatment as usual, in comparison to placebo and treatment as usual, improves the mental health of people with borderline personality disorder Secondary objectives: 1. To examine whether the addition of quetiapine improves social and occupational functioning, quality of life and reduces the incidence of suicidal behaviour in comparison to placebo and TAU 2. To compare the levels of adherence and the incidence of side-effects, including change in weight, amongst those prescribed quetiapine and those prescribed placebo. Economic Objective: To examine the cost, cost-effectiveness and cost-utility of adding quetiapine to TAU for adults with BPD in comparison to placebo and TAU. Background and study aims Borderline personality disorder (BPD) describes a collection of problems including negative feelings about self, fears of being let down, an acute sense of abandonment and rapid, distressing changes in mood. People with BPD find it difficult to maintain relationships, have high levels of mental health problems like depression and drug misuse, and high rates of self-harm and suicide. There are currently no drugs licensed for the treatment of BPD and clinicians are often unsure how best to help people with BPD. Quetiapine is the most widely prescribed antipsychotic medication for BPD in the UK despite limited evidence that it works. There is only one published trial of quetiapine for BPD treatment which found that quetiapine was more effective than a ‘dummy tablet’ (placebo) in improving symptoms of BPD. However, the trial was short with a small number of participants so a longer and larger trial of quetiapine is required to see if these promising results can be repeated. It would be a very important finding and provide evidence for use of quetiapine to treat BPD. If the result does not provide evidence of the benefits of quetiapine, then clinicians would review whether treatment with quetiapine should be continued. Who can participate? We will recruit people in contact with mental health services in the NHS in regions in England that are under-represented in mental health research. What does the study involve? In this trial, people with BPD will be allocated, by chance, to receive either placebo or quetiapine for 12-months alongside their usual treatment. We will also examine any changes in cost that result from prescribing this drug and whether any changes in costs are worthwhile in terms of improvements in outcomes. What are the possible benefits and risks of participating? Not provided at time of registration Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? March 2025 to October 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? questtrial@liverpool.ac.uk 1. Symptoms of BPD at 12 months using the total score on the ZAN BPD from baseline to 12 months 1. Standardised Assessment of Personality Abbreviated Scale at 12 months using SAPAS at baseline and 12 months 2. Total score on the ZAN-BPD over 12 months measured at baseline, 3, 6, 9 and 12 months 3. Total score on the 21 item Beck Depression Inventory at baseline, 3, 6 and 12 months. 4. Mood Instability using the Affective Lability Scale – Short Form at baseline, 3, 6 and 12 months 5. Incidence and severity of suicidal behaviour and self-harm using the Deliberate Self-Harm Inventory at baseline, 6 and 12 months 6. Self-Reported Version of ZAN BPD at baseline, 3, 6, 9 and 12 months 7. Social functioning measured via the Work and Social Adjustment Scale (WSAS) at baseline, 6 and 12 months 8. Health-related quality of life measured using EuroQoL-5D-5L at baseline, 6 and 12 months 9. Side effects using the Antipsychotic Non-Neurological Side Effects Scale (ANNSERS) at baseline, 3, 6, 9 and 12 months 10. Medication adherence using the Brief Adherence Rating Scale (BARS) at 3, 6, 9 and 12 months 11. Use of alcohol and other drugs via ASSIST-Lite at baseline, 6 and 12 months 12. Body Weight in Kg at baseline and 12 months 13. Serious adverse events up to 12 months 14. Use of rescue medication at 6 and 12 months 15. Sleep Disturbance using PROMIS Sleep Disturbance -Short Form at baseline, 3, 6, 9 and 12 months 16. Use of health and social services using the ADSUS at baseline, 6 and 12 months Ethics approval required West Midlands - Edgbaston Research Ethics Committee

2 Redman Place, Stratford

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

V7 Building Kings Business Park Kings Drive

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

Elizabeth House, Fulbourn Hospital Fulbourn

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

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Fulbourn Hospital

Cambridge Road Fulbourn

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

High St

Winsford England CW7 2AS Rowan View

Maghull Health Park

Liverpool England L31 1HW RW40C@2.16.840.1.113883.2.1.3.2.4.18.48 Phoenix Service

The Barberry 25 Vincent Drive

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

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

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

Parkbourn

Liverpool United Kingdom L31 1HW +44 151 472 4045 inti.qurashi@merseycare.nhs.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 11752949 true Targeting non-small cell lung cancer with Doggybone personalised cancer DNA vaccines (dbPCV) NEOVACC The main objective of the trial is to test whether it is possible to produce the NeoVACC personalised vaccine (dbPCV) in a timely manner. The secondary objectives are as follows:- 1. To assess whether the NeoVACC personalised vaccine (dbPCV), administered alongside standard of care treatment with pembrolizumab, is safe and can be tolerated by participants. 2. To find out how many participants' cancer shrinks or disappears after receiving their NeoVACC personalised vaccine (dbPCV) and standard of care treatment with pembrolizumab. There is also an exploratory objective:- 1. To look at the participant's immune system response to receiving the NeoVACC personalised vaccine (db-PCV). Background and study aims Personalised cancer vaccines (PCV) are a new approach for training a person’s immune system to attack the cancer. In this trial for patients with non-small cell lung cancer (NSCLC), each person receives a unique vaccine, made from their own genetic information (DNA), called a doggybone vaccine. The vaccine will be added to a common therapy for NSCLC, a drug called pembrolizumab. Pembrolizumab is used on its own to treat NSCLC if at least 50% of the cancer cells show a molecule called PDL1 (programmed-death ligand 1). A key aim of the study is to work out if the vaccine can train the immune system in the desired way and if this links to an improvement in the cancer. Who can participate? Adult patients with histologically proven advanced or recurrent NSCLC with PDL1 expression ≥50% and where anti-PD1 immunotherapy is licensed as standard of care treatment What does the study involve? Pembrolizumab is given for up to 2 years but may be stopped early if it does not work or if it causes side effects that make it unsafe to continue. A small sample of the cancer tissue (biopsy) will be taken to look at the genetic differences in cancer cells compared to normal cells. This genetic information will be used to make the vaccine. Participants will continue pembrolizumab treatment at the same time. When the vaccine is ready, participants will receive their own vaccine every 3 weeks for 24 weeks and every 6 weeks for the remainder of the time the participant is in the trial. The vaccine will be given into a muscle, using a needle-free injector called the PharmaJet. Pembrolizumab and vaccine treatment will continue at the same time for up to a maximum of 2 years. PCVs have been safe in other trials but every participant will be followed carefully for side effects. The cancer will be monitored carefully, a second cancer biopsy will be collected during treatment, as well as blood samples over time and on two occasions a larger sample of some blood cells (white blood cells) in a process called leukapheresis. These samples will be used to see whether the vaccine has trained participant cells to recognise and fight the cancer. What are the possible benefits and risks of participating? The expected benefit from the NEOVACC trial is the training of a person’s immune system to fight their cancer. It is unknown how well the vaccine will work and it is being investigated in humans for the first time. It is hoped that this trial will help show how the immune system responds to the NEOVACC personalised cancer vaccine. In the future, this may then help patients with NSCLC or many other types of cancer. The expected risks: Blood samples: Where possible, these will be taken at the same time as routine blood sampling. Risks include some discomfort and bruising. Leukapheresis: Risks include bruising, numbness to hands and feet from a drop in blood calcium levels. It will be performed by highly trained staff. Participants are closely monitored and staff are present to treat any side effects. Research leukapheresis is a safe, effective way of obtaining large numbers of white blood cells required for translational research. Research bronchoscopy/EBUS/Navigational bronchoscopy: Risks of bronchoscopy include sedation, bleeding, discomfort, pneumothorax (<1%) and a small risk of death (1¬2 in 10000). Sedation risk will be minimised by using the least amount of sedation necessary with full monitoring and having reversal agents present for use if required. Bleeding risk is minimised by ensuring platelet counts and clotting are within safe parameters and use of cold saline or adrenaline to achieve haemostasis if necessary. Discomfort will be minimised by using anti¬tussives and local anaesthetic. There is a small risk of pneumothorax (<1%) if transbronchial biopsies/lymph node biopsies are performed, the participant will have a chest radiograph prior to discharge to ensure they do not have a pneumothorax if necessary. The risk of death is minimised by an experienced bronchoscopist reviewing the participant to ensure they are fit to undergo the bronchoscopy. Serial research bronchoscopies are well tolerated and are an established common investigation for many lung diseases. Having research bronchoscopies entails coming to the hospital for a few hours each time, which can be inconvenient to the participant. Research CT/USS guided biopsy: Risks are similar to any CT or Ultrasound guided biopsy. Risks include bleeding and a 5-7% risk of a collapsed lung that requires a chest tube. Bleeding risk is minimised by ensuring the participant's platelet count and clotting are within safe parameters. Discomfort will be minimised by using local anaesthetic. The risk of pneumothorax is managed by careful participant selection and involvement of specialist interventional radiologists in a tertiary specialised Heart and Chest hospital. Having research image-guided biopsies entails coming to the hospital for a few hours each time, which can be inconvenient for participants. Surgical research biopsy: Risks include pain, bleeding, infection, risk of a collapsed lung, small risk of death and risks associated with a general anaesthetic. The surgeon will detail the specific risks. Standard measures will be taken to minimise risks of pain, bleeding and infection. Risks are minimised by involving the thoracic surgeons' significant experience and expertise. Having research surgical biopsies entails coming to the hospital for up to a few days each time, which may be inconvenient to the participant. Trial drug (NeoVACC): This is the first clinical trial of personalised doggybone DNA cancer vaccination (NeoVACC) in participants, therefore it is not known if there will be any side effects in humans. Participants will be carefully screened to ensure they are suitable for the trial and will be monitored carefully for side effects throughout the trial and treated as required. This will include regular reviews with examinations and blood tests. There is a dedicated 24-hour phone number for participants to contact the hospital if they feel unwell or to seek advice during treatment. To minimise the burden of additional hospital visits on participants, most of the follow-ups will take place alongside standard of care visits. The effects of the vaccine on an unborn foetus or a breastfeeding infant are unknown. As a result, women who are pregnant, breastfeeding or thinking of becoming pregnant will not be able to take part in the trial. To minimise this risk, if there is a chance a participant could become pregnant, they must have a negative pregnancy test at Screening and Baseline visits and before each treatment cycle to be able to take part in the trial. During the trial, all participants must agree to use a highly effective method of contraception and for 4 months after the final vaccination. Radiation risk: Participants in this trial will have CT scans as part of their standard care. They may have up to 2 further research CT scans or cone beam CT scans (+/- fluoroscopy) to guide biopsies with CT guided biopsy or navigational bronchoscopy. These procedures use ionising radiation which may cause cancer many years or decades after exposure. In participants with this type of cancer, the chances of this happening as a consequence of taking part in this study are less than 1%. Participants may also undergo non-ionising radiation from ultrasound used in bronchoscopy with endobronchial ultrasound or an ultrasound guided biopsy. Where is the study run from? University of Liverpool, UK When is the study starting and how long is it expected to run for? February 2025 to November 2027 Who is funding the study? 1. United Kingdom Research and Innovation (UKRI) 2. Medical Research Council Who is the main contact? NEOVACCTrial@liverpool.ac.uk Feasibility of making and delivering the dbDNA vaccines is measured by confirming whether the NEOVACC personalised vaccines (dbPCV) were delivered in a timely manner at the time of first vaccination. Secondary outcome measures: 1. Safety and tolerability of vaccination in combination with anti-PD1 is measured using adverse event reporting and clinical, biochemical and radiological assessments from first vaccination to end of treatment (up to 2 years as standard of care anti-PD1 treatment). 2. Overall Response Rate is measured using CT scan chest/abdomen/pelvis at screening, baseline, week 12, week 24 and then every 12 weeks during treatment and at the end of trial, as per standard of care imaging. 3. Time to disease progression is measured using CT scan chest/abdomen/pelvis at screening, baseline, week 12, week 24 and then every 12 weeks during treatment and at the end of trial, as per standard of care imaging. 4. Overall survival is measured at the end of trial. Exploratory Outcome Measure: Vaccine induced T cell response is measured using ELISPOT on blood samples, ELISA on plasma samples, single cell RNA and TCR sequencing in blood and tissue samples; and immunofluorescence of protein expression in tissue. This will be measured throughout the trial using blood samples, tissue sampling after 6 doses of the dbDNA vaccine, and FPE tissue related to skin or bowel toxicities collected as part of standard of care and surplus to diagnostic requirement. Ethics approval required London – West London & GTAC Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/LO/0177 10.1186/ISRCTN11752949 1010332 CPMS: 66997, UoL001847 1010332 66997 UoL001847 Single arm non-randomized study Interventional Non randomised study Efficacy Safety 2027-11-30T00:00:00.000Z United Kingdom England Clatterbridge Cancer Centre

Clatterbridge Hospital Clatterbridge Road

Wirral England CH63 4JY RJR62@2.16.840.1.113883.2.1.3.2.4.18.48 Patient false 1. Written and informed consent obtained from the participant and agreement from the participant to comply with the requirements of the trial. 2. Aged ≥ 18 years old. 3. Histologically proven advanced or recurrent NSCLC with PDL1 expression ≥50% and where anti-PD1 immunotherapy is licensed as standard of care treatment. 4. Has completed at least 3 cycles of SOC IO and demonstrates partial response, stable disease or progression deemed to be such that can wait for production of PCV. 5. Tumour accessible for sufficient sample to be taken for research e.g. surgical biopsy or repeat core biopsies (6 passes) in the opinion of the treating oncologist and physician performing the biopsy. 6. Considered fit enough to undergo trial specific procedures. 7. ECOG performance status of 0-1. 8. Venous access sufficient for collection of the blood/apheresis samples. Mixed 18 Years 100 Years All 15 0 1. Demonstrated a complete response from previous treatments according to RECIST criteria. 2. In the physician’s view are likely to have sufficient benefit from anti-PD1 treatment alone. 3. Evidence of rapid disease progression, who cannot wait for vaccine production and must seek alternative treatment options. 4. Active autoimmune disease likely to pose a risk for the safe administration of anti-PD1 or other immune activating agents; exceptions to this are atopic dermatitis and psoriasis not requiring systemic treatment. Topical and inhaled steroids are allowed. 5. Significant immune related adverse event requiring anti-PD1 to be stopped or necessitating ongoing systemic immunosuppressive treatment. Patients who have required mycophenolate or infliximab for management of IO related toxicities are not eligible. 6. Currently receiving any form of chemotherapy and have received chemotherapy in the previous 9 weeks prior to screening. 7. Any other experimental medications during trial participation and within 30 days of consent. 8. History of confirmed inflammatory bowel disease. 9. Previous organ transplantation. 10. Known brain metastases. 11. Greater than 10mg Prednisolone equivalent per day unless for replacement purposes (e.g. adrenal insufficiency). 12. Active or previous malignancies of other types, which in the Investigator’s opinion would mean they are not a good candidate for the clinical trial; specifically excluded are patients with malignancies that even in the early stages carry a high immunosuppressive burden (for example CLL, Multiple myeloma). 13. Received anti-PD1 or anti-PD-L1 in prior line of treatment. 14. Other vaccination within a week of trial vaccination. 15. Known diagnosis of HIV or active hepatitis B or C. Participants who are HBV carriers and receiving anti-viral prophylaxis are excluded. 16. Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the participant’s ability to provide informed consent and undergo trial procedures. 17. Women of child bearing potential (WOCBP) who are currently pregnant, lactating or breastfeeding. 18. WOCBP or participants with partners of child bearing potential who are unable or unwilling to use contraception during the trial. 19. Known allergy to any component of the IMP. 2025-09-30T00:00:00.000Z 2026-12-31T00:00:00.000Z Non-small cell lung cancer (NSCLC) with PDL1 expression ≥50% which does not achieve tumour clearance with anti-PD1 treatment Cancer The NEOVACC doggybone personalised cancer vaccines (dbPCV) will be administered by PharmaJet Stratis Needle-free injection system. Participants will receive a 2mg/ml dose of dbPCV in 2 divided doses of 0.5ml every 3 weeks for the first 24 weeks of treatment and then every 6 weeks for the remainder of participation in the trial. The dbPCV will be given on the same day and prior to SOC anti PD1 treatment for a maximum total of 18 vaccinations over 24 months. Any dose delays in anti-PD1 treatment will be followed by dose delays in administration of the vaccine. There are no dose modifications. Drug Phase I NEOVACC Doggybone Personalised Cancer Vaccine (dbPCV) [dbDNA drug substance] Data sharing statement to be made available at a later date f862ffb2-5dcc-4273-88a8-3ba5e29cec0c db6132b4-99c9-4f28-a506-8df84588fe3c a3456b92-2ff6-414c-92bb-f8d1a20b0f46 c4e14863-4030-4bc0-8aa1-707e91558bca bdd69119-a733-4a9d-89a7-ac6377fd6444 No Christian Ottensmeier Scientific Principal investigator

Department of Molecular and Clinical Cancer Medicine University of Liverpool 2nd Floor William Henry Duncan Building University of Liverpool 6 West Derby Street

Liverpool United Kingdom L7 8TX +44 (0)151 795 8320 C.Ottensmeier@liverpool.ac.uk Public Helen Eccleson Public

Liverpool Clinical Trials Centre University of Liverpool 1st Floor Block C Waterhouse Building 3 Brownlow Street

Liverpool United Kingdom L69 3GL - NEOVACCTrial@liverpool.ac.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial UK Research and Innovation http://dx.doi.org/10.13039/100014013 Medical Research Council http://dx.doi.org/10.13039/501100000265 17400289 true MOVE SMART – a feasibility study to assess design of a randomised controlled clinical trial of a sedentary interruption intervention to improve health outcomes for patients with psoriasis MOVE SMART A randomised clinical trial of a novel physical behaviour intervention called MOVE SMART is a feasible research proposition and acceptable to patients with psoriasis. Background and study aims People with psoriasis are less active than others. Psoriasis can lead to heart disease and other conditions. Being more active could prevent this. Therefore, an exercise programme for people with psoriasis will be created. It is expected that being more active will improve psoriasis and reduce the risk of heart disease. Patients will likely find their well-being and physical ability improved too. However, people may still spend long periods sitting/lying down, which is also damaging to health. MOVE SMART will be developed to help people be more active and spend less time sitting down. The study aims to find out if MOVE SMART helps psoriasis and other conditions linked with psoriasis. To do that, a clinical trial will be necessary. The aim of this study will be to determine whether a clinical trial is possible or not. Who can participate? Patients with psoriasis aged between 18 and 60 years old What does the study involve? The study will last 24 weeks. All volunteers will continue with their usual treatment and have an equal chance of being in the MOVE SMART group. MOVE SMART will last for 12 weeks. Volunteers will do activities of their own choice during weeks 13-24. MOVE SMART will prompt 2 minutes of activity (only) after 30 minutes of sitting/lying down. In Workstream 1, volunteers will wear a small monitor (on their wrist/thigh) to measure activity and sitting time. At Week 1, Week 12, and Week 24, all volunteers will self-assess their psoriasis and wellbeing. The study team will assist with this. Blood will be collected at these time points using finger-prick kits. Blood pressure and body weight will also be recorded. Physical ability will be measured. In Workstream 2, feedback on MOVE SMART will be gathered, and the proposed clinical trial will be finalized in Workstream 3. What are the possible benefits and risks of participating? The benefits of this study will include the opportunity to follow MOVE SMART, a new lifestyle programme for patients with psoriasis. Preliminary research suggests that this may help psoriasis and other health conditions linked to psoriasis. There will be no clinic or hospital visits required, and all study activities can be completed at home. Participation in this study will involve minimal risk, which will be managed through appropriate training and support from the study team. Where is the study run from? The University of Manchester will lead this research project, working in collaboration with colleagues at Manchester Metropolitan University, The University of Liverpool, and Salford Royal Hospital/Northern Care Alliance NHS Foundation Trust. When is the study starting and how long is it expected to run for? June 2022 to October 2027 Who is funding the study? The study will be funded by a research grant from the National Institute for Health and Care Research (NIHR) and sponsored by The University of Manchester. Recruitment will be through an expression of interest directly to the research team. Who is the main contact? Dr Helen Young, The University of Manchester, helen.s.young@manchester.ac.uk Clinical utility in the management of psoriasis measured using the Psoriasis Area and Severity Index (PASI) self-assessment questionnaire at baseline, week 12 and week 24 1. Feasibility of the research processes and delivery of the intervention measured via: 1.1. Recruitment rate measured using a tally of participants recruited to study in the collected study data at baseline and week 24 1.2. Retention rate measured using a tally of participants starting and completing the study in the collected study data at week 24 1.3. Total clinical assessments completed measured using the following self-assessment questionnaires at baseline, week 12 and week 24: 1.3.1. Psoriasis Area and Severity Index (PASI) 1.3.2. Dermatology Life Quality Index (DLQI) 1.3.3. Pittsburgh Sleep Quality Index (P Sleep QI) 1.3.4. Routine Assessment of Patient Index Data 3 (RAPID3) 1.3.5. Psoriatic Arthritis Impact of Disease 12-item (PsAID12) 1.3.6. EuroQol 5-Dimension 5-Level (EQ 5D 5L) 1.4. Capillary-blood self-collection completed measured using a tally of blood collection returns received by the study team in the collected study data at baseline, week 12 and week 24 1.5. Adherence to intervention measured using an accelerometer over 1 week to count activity and sedentary time at baseline, week 6, week 12 and week 24 2. Acceptability of the intervention measured using the 5-point Likert score from the phase 1 survey at week 12 3. Acceptability of the trial processes measured using the 5-point Likert score from the phase 2 survey at week 24 Ethics approval required North West - Greater Manchester West Research Ethics Committee

Barlow House, 3rd Floor, 4 Minshull Street

Manchester United Kingdom M1 3DZ 24/NW/0362 10.1186/ISRCTN17400289 335248 CPMS: 58898, NIHR: 207157 335248 58898 207157 Randomized controlled trial Interventional Randomised controlled trial Treatment 2027-10-31T00:00:00.000Z United Kingdom England University of Manchester

Faculty of Biology, Medicine and Health School of Biological Sciences Division of Musculoskeletal and Dermatological Sciences Oxford Road

Manchester England M13 9PG Salford Royal

Stott Lane

Salford England M6 8HD RM301@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Patients with Type 1 chronic plaque psoriasis (disease onset before age 40 years) with/without stable psoriatic arthritis 2. Aged 18-60 years (due to the prevalence of CVD disease in the >60s in the UK, which means that we are likely to detect greater differences in CVD risk in those <60) 3. Stable disease but measurable residual psoriasis/psoriatic arthritis 4. No treatment/dose changes for 2 months 5. High sedentary time (irrespective of level of physical activity): defined using the the Short Form International Physical Activity Questionnaire (IPAQ) as >8 hours per day Adult 18 Years 60 Years All 60 70 1. Unable to rise from a sitting to a standing position, walk around a room (independently or aided by a walking stick, frame or trolly) whilst maintaining a steady pace (~30 steps/minute) for 2 minutes without stopping. 2. Worsening inflammatory arthritis or the presence of other significant comorbid conditions that would interfere with the ability to participate in physical activity or the study protocol, such as severe cardiovascular disease, severe chronic obstructive pulmonary disease (COPD), or any other condition as determined via the health questionnaire. 3. Regularly engaging in HIGH levels of physical activity (as defined by IPAQ) whilst spending MINIMAL time in sedentary activities during day-waking hours (as calculated by IPAQ,<6 hours per day). 2025-02-01T00:00:00.000Z 2026-06-03T00:00:00.000Z Psoriasis Skin and Connective Tissue Diseases The study will last 24 weeks. All volunteers will continue with their usual treatment and have an equal chance of being randomly allocated to the MOVE SMART group using a stratified randomisation procedure. MOVE SMART will last for 12 weeks. Volunteers will do activities of their own choice during weeks 13-24. MOVE SMART: The purpose of MOVE SMART is to interrupt bouts of prolonged sedentary behaviour with light-intensity physical activity, thus reducing overall sedentary time. Its design is based upon two key points. First, WHO recommendations on physical activity together with our published data give a theoretical starting point for the amount of physical activity which may be beneficial. Second, fragmentation of sitting time every 30-minutes over a 12-hour period (09:00-21:00), is based upon recent epidemiological evidence linking a more prolonged sedentary accumulation pattern (≥30-minute bouts) with greater all-cause mortality. MOVE SMART will be confined to a 12-hour period between 09:00 and 21:00 and will involve up to 24 2-minute bouts (48 minutes) of upright light-intensity physical activity throughout the day. An important aspect is that participants engage in light-intensity physical activities which are ADDITIONAL to their physical activity at baseline. Participants will utilise a free Mobile Application on their smartphone which will be customised to prompt physical activity following 30-minutes of sedentary behaviour. It is important to note that the Application will ONLY alert when/if a participant remains sedentary (without moving) for 30-minutes or more. The advantage of this Application over other prompting devices is that it can be programmed to avoid alarm fatigue (borne out of iterative testing by our PPI advisors), which could lead to participants ignoring movement prompts and negatively affecting intervention compliance. On receiving an alert participants will undertake 2 minutes of light-intensity physical activity and will perform a mixture of body weight only (such as walking around the home, office, or outdoors at a steady pace, side-to-side steps, Tai Chi movements) and aided-resistance work using resistance bands (Thera-bands) which will be supplied at the start of the study. Importantly, participants will have autonomy in selecting the specific type of physical activity they wish to follow. To enhance the clarity of instruction, each recommended activity will be meticulously documented in a comprehensive illustration booklet. Behavioural The (fully anonymised) datasets generated during and/or analysed during the current study will be stored in a publicly available repository ( approved by The University of Manchester). Consent from participants will be obtained for this purpose. Stored in publicly available repository 2026 Protocol article in https://pubmed.ncbi.nlm.nih.gov/41838662/ (added 31/03/2026) Protocol

ef93e444-59b5-4d8d-938e-bb88e3057a6a 488d38aa-f147-45ae-b841-0e4679148766 4c76a9d1-30e3-4674-ae58-7635ce6ca576 aecec9a9-26dd-4763-946c-bac115d35af7 af38d077-ac17-451e-b14b-cb3f6108fbd6 6a6b8ac2-f435-41e3-b0a6-3ad3e3a044c1 193ec291-d197-404b-b33e-25321d290f07 109d5ad0-1c0f-4f13-8d1d-e164bc68b7c9 Yes Protocol file 46181_Protocol_v2_18Sept2024.pdf d3e660ec-5125-451c-98f1-755440221e0d true application/pdf 450792 6fe6120ab3b5203a36a0ce8c8f806832 Protocol file ISRCTN17400289 MOVE_SMART_Protocol_v3_13Dec2024.pdf 400ac274-9bab-4fa8-9bd8-99a3f0a2727c true application/pdf 396547 a475ba62004e44db3c8b198ebfc6e5a2 Helen Young https://orcid.org/0000-0003-1538-445X Principal investigator

Clinical Senior Lecturer in Dermatology and Consultant Dermatologist Department of Dermatology The University of Manchester Salford Royal Hospital Stott Lane

Salford United Kingdom M6 8HD +44 (0)161 206 0523 helen.s.young@manchester.ac.uk Public Gladys Pearson https://orcid.org/0000-0002-1466-3265 Scientific

Faculty of Science & Engineering Department of Sport and Exercise Sciences Manchester Metropolitan University Institute of Sport Building 99 Oxford Road

Manchester United Kingdom M1 7EL +44 (0)161 247 5594 g.pearson@mmu.ac.uk Public Ben Ives https://orcid.org/0000-0002-7262-0693 Scientific

Faculty of Science & Engineering Department of Sport and Exercise Sciences Manchester Metropolitan University Institute of Sport Building 99 Oxford Road

Manchester United Kingdom M1 7EL - b.ives@mmu.ac.uk Public Girvan Burnside https://orcid.org/0000-0001-7398-1346 Scientific

Liverpool Clinical Trials Centre University of Liverpool 2nd Floor Institute in the Park Alder Hey Children’s NHS Foundation Trust Eaton Road

Liverpool United Kingdom L12 2AP - g.burnside@liverpool.ac.uk Public Russ Cowper Public

The University of Manchester FBMH, School of Biological Sciences Division of Musculoskeletal and Dermatological Sciences Salford Royal NHS Foundation Trust

Salford United Kingdom M6 8HD - rascalrussky@googlemail.com Public Emma Bedson https://orcid.org/0000-0001-5209-1854 Scientific

Liverpool Clinical Trials Centre University of Liverpool

Liverpool United Kingdom L12 2AP +44 845 68 00 951 ebedson@liverpool.ac.uk Public University of Manchester Hospital/treatment centre https://ror.org/027m9bs27 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 63161604 true Restart tICrH: a randomised trial of timing to restart direct oral anticoagulants after traumatic intracranial haemorrhage RESTART tICrH Primary objective: To compare the clinical effectiveness of restarting/starting direct oral anticoagulant (DOAC) early (1 week) versus late (4 weeks) following traumatic intracranial haemorrhage (tICrH). Secondary objectives: 1. To evaluate the safety of treating patients restarting/starting DOAC early (1 week) in comparison to late (4 weeks) 2. To evaluate functional status and quality of life for patients restarting/starting DOAC early (1 week) in comparison to late (4 weeks) 3. To determine patient/carer attitudes to restarting/starting DOAC post-traumatic intracranial haemorrhage (tICrH) 4. To estimate the cost-effectiveness of restarting/starting DOAC early (1 week) in comparison to late (4 weeks) Background and study aims Older people falling from a standing height is the most common cause of hospital admission for head injury. Up to 1 in 3 patients admitted are taking a tablet medication which thins the blood, known as an oral anticoagulant. This type of medication can increase the likelihood of bleeding in the brain. Many patients are taking oral anticoagulation due to having an irregular heartbeat (called atrial fibrillation) or because of having a previous stroke or blood clots. When a scan shows blood in the brain, oral anticoagulation is nearly always stopped. However, this leaves the question of when it is safe to restart them. The risk of making the bleeding in the brain worse must be balanced against the risk of having a stroke or blood clots. There is no clear evidence on the safest time to restart oral anticoagulation, but most neurosurgeons advise restarting them 1-4 weeks after head injury. The number of people who have a bleed on their brain after a head injury is increasing and further brain bleeding or a stroke can have a serious effect on patients' lives and their ongoing healthcare needs. The main purpose of the trial is to determine when is the most beneficial time for people to start or restart a direct oral anticoagulant (DOAC) after their head injury. Who can participate? Patients aged 18 years and over admitted to hospital with a bleed on the brain caused by a head injury who were taking oral anticoagulation before their head injury and have been prescribed a DOAC for a previously diagnosed medical condition (e.g., atrial fibrillation). Patients on other oral anti-coagulants such as warfarin may also be able to take part. What does the study involve? People will be asked to start the medication either 1 week or 4 weeks after their head injury. This will be randomly assigned by a computer. They will be then followed closely for 26 weeks and any major bleeding events or blood clots (thrombotic events) such as a stroke or heart attack will be recorded. What are the possible benefits and risks of participating? Both timepoints for restarting oral anticoagulants have been shown to improve symptoms but it is not known which timescale is best. In normal clinical care patients will restart oral anticoagulants 1-4 weeks after head injury so this study will not put participants at any additional risk. Participants will receive only CT or MRI scans as they would normally for standard of care so there is not expected to be any additional risk for participants. Where is the study run from? Liverpool Clinical Trials Centre (UK) When is the study starting and how long is it expected to run for? August 2024 to May 2028 Who is funding the study? Health Technology Assessment Programme (UK) Who is the main contact? Dr Laura Wright, restart.trial@liverpool.ac.uk The proportion of patients with critical haemorrhagic or thrombotic events within 12 weeks following traumatic intracranial haemorrhage (tICrH), measured using case report form Current secondary outcomes as of 11/06/2026: 1. Time to first haemorrhagic or thrombotic event within 12 weeks, measured using case report form 2. Time to first haemorrhagic event within 12 weeks, measured using case report form 3. Time to first thrombotic event within 12 weeks, measured using case report form 4. Time to death measured at 12 and 26 weeks, measured using case report form 5. Functional outcome measured using modified Rankin Scale (mRS), Barthel Index and extended Glasgow Outcome Scale (GOS-E) at 26 weeks 6. Quality of life measured with EQ-5D-5L at 12 and 26 weeks 7. Patient/caregiver attitudes to restarting DOAC following tICrH within 60 days of study approach, collected using a semi-structured interview 8. Healthcare resource use, measured using case report form and routine data at 12 and 26 weeks 9. Incremental cost per quality-adjusted life year (QALY) gained, measured using case report form and routine data at 12 and 26 weeks Previous secondary outcomes: 1. Time to first haemorrhagic or thrombotic event within 12 weeks, measured using case report form 2. Time to first haemorrhagic event within 12 weeks, measured using case report form 3. Time to first thrombotic event within 12 weeks, measured using case report form 4. Time to death measured at 12 and 26 weeks, measured using case report form 5. Functional outcome measured using modified Rankin Scale (mRS), Barthel Index and extended Glasgow Outcome Scale (GOS-E) at 12 and 26 weeks 6. Quality of life measured with EQ-5D-5L at 6, 12 and 26 weeks 7. Patient and caregiver attitudes to recommencing DOAC following tICrH within the first 9 months of recruitment start, collected using a semi-structured interview 8. Incremental cost per quality-adjusted life year (QALY) gained, measured using case report form and routine data at 6, 12 and 26 weeks Ethics approval required South Central – Berkshire Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/SC/0298 10.1186/ISRCTN63161604 1008878 NCT06322953 CPMS: 65417, RG442-21 NCT06322953 1008878 65417 RG442-21 Open randomized controlled parallel-group trial Interventional Randomised controlled trial Efficacy Safety 2028-05-31T00:00:00.000Z United Kingdom England Not provided at time of registration

-

- England - Patient Current participant inclusion criteria as of 11/06/2026; 1. Informed consent obtained from the participant/participant’s legal representative and ability to comply with the requirements of the trial 2. Adult ≥18 years with traumatic intracranial haemorrhage (tICrH) in the past 1 week who were taking oral anticoagulants (OAC) prior to admission (Oral anticoagulants include any DOAC or Vitamin K antagonist (e.g. Warfarin), prescribed for atrial fibrillation (AF)/ atrial flutter, or venous thromboembolism (VTE) prior to admission for tICrH) Previous participant inclusion criteria as of 06/06/2025: 1. Informed consent obtained from the participant/participant’s legal representative and the ability to comply with the requirements of the trial 2. Adult ≥18 years with traumatic intracranial haemorrhage (tICrH) in the past 1 week who were taking oral anticoagulants (OAC) prior to admission (Oral anticoagulants include any DOAC or Vitamin K antagonist (e.g., warfarin), prescribed for atrial fibrillation (AF) or venous thromboembolism (VTE) prior to admission for tICrH) 3. At high risk for thromboembolic complications (CHA2DS2-VASc ≥2 in men and ≥3 in women) OR patients taking long-term OAC for deep vein thrombosis (DVT) / pulmonary embolism (PE) Previous participant inclusion criteria: 1. Informed consent obtained from participant/participants’ legal representative/participants’ Consultee and ability to comply with the requirements of the trial 2. Adult ≥18 years with traumatic intracranial haemorrhage (tICrH) in the past 1 week who were taking oral anticoagulants (OAC) prior to admission 3. Oral anticoagulants include any DOAC or Vitamin K antagonist (e.g., warfarin), prescribed for atrial fibrillation (AF) or venous thromboembolism (VTE) prior to admission for tICrH 4. At high risk for thromboembolic complications (CHA2DS2-VASc ≥2 in men and ≥3 in women) Mixed 18 Years 100 Years All 1084 0 Current participant exclusion criteria as of 11/06/2026: 1. Patients whose traumatic intracranial haemorrhage is a chronic subdural haematoma only 2. Patients with a mechanical heart valve 3. Patients with a plan to start/restart anti-platelet therapy within 12 weeks of tICrH 4. Severe polytrauma or life-threatening injury where there is a contraindication to restarting anticoagulation 5. Pregnant or nursing female 6. For participants of reproductive potential (males and females), not willing to use of a reliable means of contraception* 7. Participants with a hypersensitivity or contraindication to Direct Oral Anticoagulant (DOAC) as detailed in each IMP SmPC 8. Participant with bleeding where it would be unsafe to restart DOAC at 1 week 9. Participant with clinical reason to restart DOAC before 4 weeks or complete within 12 weeks 10. Indication to stay on VKA (Warfarin) rather than switching to DOAC (e.g., severe renal impairment) Previous participant exclusion criteria as of 06/06/2025: 1. Patients whose traumatic intracranial haemorrhage is a chronic subdural haematoma only 2. Patients with a mechanical heart valve 3. Patients with a plan to start/restart anti-platelet therapy within 12 weeks of tICrH 4. Abbreviated Injury Scale other than head with a score >3 5. Pregnant or nursing female 6. For participants of reproductive potential (males and females), not willing to use a reliable means of contraception* 7. Participants with a hypersensitivity or contraindication to Direct Oral Anticoagulant (DOAC) as detailed in each IMP SmPC 8. Participant with bleeding where it would be unsafe to restart DOAC at 1 week 9. Participant with clinical reason to restart DOAC before 4 weeks or complete within 12 weeks 10. Concomitant p-gp and CYP3A4 inducers/inhibitors 11. Indication to stay on VKA (Warfarin) rather than switching to DOAC (e.g., severe renal impairment) Previous participant exclusion criteria: 1. Patients whose traumatic intracranial haemorrhage is a chronic subdural haematoma only 2. Patients with a mechanical heart valve 3. Patients with a plan to start/restart anti-platelet therapy within 12 weeks of tICrH 4. Abbreviated Injury Scale other than head with a score >3 5. Pregnant or nursing female 6. For participants of reproductive potential (males and females), not willing to use a reliable means of contraception* 7. Participants with a hypersensitivity or contraindication to Direct Oral Anticoagulant (DOAC) 8. Participant with bleeding where it would be unsafe to restart DOAC at 1 week 9. Participant with clinical reason to restart DOAC before 4 weeks or complete within 12 weeks 10. Concomitant p-gp and CYP3A4 inducers/inhibitors 11. Indication to stay on VKA (Warfarin) rather than switching to DOAC (e.g., severe renal impairment) 2025-03-10T00:00:00.000Z 2027-06-30T00:00:00.000Z Traumatic intracranial haemorrhage Injury, Occupational Diseases, Poisoning Participants will be randomised to one of the two arms using an online randomisation system: Start/Restart DOAC at 1 week – Participants will be restarted/started on DOAC 1 week post-traumatic intracranial haemorrhage Start/Restart DOAC at 4 weeks – Participants will be restarted/started on DOAC 4 weeks post-traumatic intracranial haemorrhage DOACs prescribed with dose, frequency and duration as per local standard practice. DOACs commonly used are apixaban, dabigatran etexilate mesilate, edoxaban and rivaroxaban. These are to be restarted at either 1 or 4 weeks post tICrH. Drug Phase III Apixaban, dabigatran etexilate mesilate, edoxaban tosilate, rivaroxaban Data sharing statement to be made available at a later date 33fea0bc-33fd-4810-9c15-5d1064df0661 f368c486-d028-47b5-9fdf-194820d804ec b96b6e0a-ee41-452a-a42d-53e3d661c30d c26640c4-a334-40a6-89fb-6830dfc575bc No Laura Wright Public

Block C Waterhouse Building 1-5 Brownlow Street

Liverpool United Kingdom L12 2AP +44 (0)151 795 0600 restart.trial@liverpool.ac.uk Public Catherine McMahon Scientific Principal investigator

Mayo Building Salford Royal Stott Lane

Salford United Kingdom M6 8HD +44 (0)161 789 7373 catherine.mcmahon@nca.nhs.uk Public The Walton Centre NHS Foundation Trust Hospital/treatment centre Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 36536677 true A 3-arm multi-centre randomised placebo-controlled trial of glycopyrrolate or hyoscine hydrobromide for the treatment of clozapine-induced hypersalivation GOTHIC2 Primary objective: To ascertain the efficacy of either hyoscine hydrobromide or glycopyrrolate in comparison to placebo in the treatment of CIH. Secondary objectives: 1. To establish which of glycopyrrolate or hyoscine hydrobromide, if any, is associated with fewer cognitive side-effects using a validated assessment measure. 2. To establish which of glycopyrrolate or hyoscine hydrobromide, if any, is associated with fewer ADRs. Added 01/05/2024: Exploratory objective: 1. To establish whether clozapine plasma levels are associated with clozapine ADRs (moved from secondary objectives) Updated 27/05/2026: The open-label phase was removed: Open-label objectives: 1. To increase knowledge of the safety profile of the active IMPs in the treatment of CIH. 2. To establish the effectiveness of active IMPs over the open-label phase. Background and study aims Clozapine is an antipsychotic medication used to help treat the symptoms of schizophrenia and is also sometimes used to treat other mental health conditions. It is the most effective antipsychotic medication for many people and it is important to keep taking it. Clozapine can cause different side effects and people tell us one of the most upsetting is excessive drooling. Doctors call this ‘clozapine-induced hypersalivation’ (CIH or drooling). People with CIH/drooling tell us they often have to wipe the saliva from their mouth during the day and their pillow becomes very wet at night which can sometimes make the skin on their face sore. CIH can be very embarrassing and lead to some patients wanting to stop clozapine treatment. For most patients this is not a good idea as their mental illness is likely to come back and they may need to be admitted to hospital. Currently, there is no proven treatment for CIH. The medication usually prescribed is called hyoscine but we don’t know if hyoscine helps although doctors think it might. Hyoscine can cause unpleasant side effects such as bowel problems (constipation) and thinking problems (making attention and concentration worse). Some studies suggest a different medication called glycopyrrolate might be helpful for CIH and may cause fewer thinking problems. But it may still cause other side effects like constipation. Patients have told us that it is important for them to know which medications may improve CIH and what the side effects are so they can make an informed choice about whether or not to take any of these medicines based on their mental illness symptoms and experience of side effects. Our study will find out if either hyoscine or glycopyrrolate can improve CIH/drooling by comparing patients taking these medications with patients taking a dummy treatment (placebo). If both help reduce CIH/drooling we will compare the two medications to see which one causes fewer side effects and ask which one patients prefer. Who can participate? Patients aged 18 - 65 years, with clozapine-induced hypersalivation. What does the study involve? Participants will be randomly assigned to receive either hyoscine hydrobromide, glycopyrronium bromide (glycopyrrolate), or a placebo over a period of 12 weeks. What are the possible benefits and risks of participating? Benefits: Not provided at time of registration Risks: Burden of visits and assessments: Treatment visits have been aligned with routine care clozapine clinic visits (every 4 weeks). Visits at home instead of the clozapine clinic can be arranged if participants prefer. Service users have been involved in GOTHIC2 throughout its development. The participant pathway and all patient-facing documentation have been developed with full PPIE involvement and use of the FAST-R service. Treatment Intervention: A summary of the more important risks are as follows: Hyoscine hydrobromide (Kwells): Very common side effects (more than one in 10) include feeling a bit sleepy or dizzy, eyesight being a bit blurry and having a dry mouth. Constipation is also possible. All of these side effects can also happen with clozapine (nIMP) so participants may not notice any difference. There is a very small chance participants might find it more difficult to concentrate or think clearly. The comprehensive list of undesirable effects is listed in the relevant SmPC. Side effects from a placebo are unlikely as it is a dummy capsule with inactive ingredients. The main ingredient, Magnesium stearate, is generally safe to consume but too much of it can have a laxative effect. Glycopyrronium bromide (Glycopyrrolate): Very common side effects (more than 1 in 10) include dry mouth, constipation, diarrhoea, vomiting, flushed skin, nasal congestion, having difficulty emptying the bladder (urinary retention), feeling irritable and experiencing a reduction in chest secretions. Common side effects (experienced by one in 10 to 1 in 100 people) include chest infections (including pneumonia), urine infections, feeling agitated or drowsy, nose bleeds, rash and fever. The comprehensive list of undesirable effects is listed in the relevant SmPC. Placebo side effects are unlikely as it is a dummy capsule with inactive ingredients. The main ingredient, Magnesium stearate, is generally safe to consume but too much of it can have a laxative effect. This is also a component of clozapine (nIMP). Treatment modifications: trial participants should not be prescribed any other CIH treatment. Participants are prescribed two capsules per day in week one and three capsules per day from week two until the end of treatment at week twelve. Should the treating clinician have any concerns about tolerance then the dose may be reduced in week one to one capsule per day and the dose can be reduced in weeks 2-12 to one or two capsules per day. The reduction and reason for the reduction should be recorded in the appropriate eCRF. Dose modifications: Participants who discontinue clozapine treatment should also discontinue trial treatment. The discontinuation of trial treatment and reason must be recorded in the appropriate eCRF. Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? November 2023 to August 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Ms Julie Perry, gothic2@liverpool.ac.uk Dr Inti Qurashi, Inti.Qurashi@merseycare.nhs.uk Current primary outcome as of 27/05/2026: Hypersalivation measured using the Drooling Rating Scale at Baseline, T 1, 2, 4, 6, 8, 12 Previous primary outcome: Hypersalivation measured using the Drooling Rating Scale at Baseline, T 1, 2, 4, 6, 8, 12 and Optional T16, 20, 24 1. Neuroleptic side-effects measured using the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) PROM (participant reported outcome measure) at Baseline, T 4, 8, 12 and Optional T16, 20, 24 2. Anticholinergic side effects measured using the Liverpool Anticholinergic Side-effects Scale (LASS) PROM at Baseline, T 4, 8, 12 and Optional T16, 20, 24 3. Sustained attention and Verbal Recognition Memory (VRM) measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a pre-loaded tablet device at Baseline and T12 4. Nocturnal hypersalivation measured using the Nocturnal Hypersalivation Rating Scale (NHRS) PROM at Baseline, T 1, 2, 4, 6, 8, 12 and Optional T16, 20, 24 5. Self-esteem measured using the Rosenberg Self-esteem scale (RSE) PROM at Baseline and T12 6. Hospital admission (whether for physical or psychiatric reasons) from Consent up to T12 and Optional follow-up to T24 7. Constipation measured using the Patient assessment of constipation and symptoms (PAC-SYM) at Baseline, T4, 8, 12 and Optional T24 8. Social functioning measured using the Personal and Social Performance scale (PSP) conducted via interview at Baseline and T12 9. Symptoms of schizophrenia measured using the Positive and negative syndrome scale (PANSS) conducted via interview at Baseline and T12 10. Effect and tolerability of treatment measured by premature discontinuation of study treatment/Continuation at T12 11. Discontinuation of clozapine 12. Serious Adverse Events reported from Consent up to T12 and Optional follow-up to T24 Updated 01/05/2024: Exploratory outcome measure: 1. Clozapine plasma levels from blood analysis at Baseline and T12 (moved from secondary outcome measures) Ethics approval required London - Fulham Research Ethics Committee

2 Redman Place, Stratford

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

V7 Building Kings Business Park Kings Drive

Prescot England L34 1PJ RW4@2.16.840.1.113883.2.1.3.2.4.18.48 South London and Maudsley NHS Foundation Trust

Bethlem Royal Hospital Monks Orchard Road

Beckenham England BR3 3BX RV5@2.16.840.1.113883.2.1.3.2.4.18.48 Greater Manchester Mental Health NHS Foundation Trust

Prestwich Hospital Bury New Road Prestwich

Manchester England M25 3BL RXV@2.16.840.1.113883.2.1.3.2.4.18.48 Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1 50 Summer Hill Road

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

225 Old Street

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

Trust Management Lydeard House Musgrove Park Hospital

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

Sentinel House 4-6 Nuffield Road Nuffield Industrial Estate

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

St. Davids Hospital Cowbridge Road East

Cardiff Wales CF11 9XB V11409@2.16.840.1.113883.2.1.3.2.4.18.48 South West Yorkshire Partnership NHS Foundation Trust

Trust Headquarters Fieldhead Hospital Ouchthorpe Lane

Wakefield England WF1 3SP RXG@2.16.840.1.113883.2.1.3.2.4.18.48 Cornwall Partnership NHS Foundation Trust

Carew House Beacon Technology Park Dunmere Road

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

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

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

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

Parkbourn

Liverpool United Kingdom L31 1HW +44 151 472 4045 Inti.Qurashi@merseycare.nhs.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 37422164 true 3-Pillars Study: a phase II open label study of the cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole, trastuzumab plus tucatinib as neoadjuvant treatment for ER-positive, PgR-positive and HER2-positive early breast cancer in post-menopausal women 3-Pillars Study Primary objective: To assess the pathological complete response rate after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib Secondary objectives: 1. To assess change in Ki67 proliferation index after 2 weeks and 23 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 2. To assess the radiological response rate as measured by ultrasound/MRI/mammogram after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 3. To assess objective clinical response rate after 24 weeks of Palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 4. To assess the proportion of tumours with a Preoperative Endocrine Prognostic Index (PEPI) score of 0 or 1 after 24 weeks of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib 5. To assess the safety and tolerability of palbociclib treatment in combination with letrozole, trastuzumab plus tucatinib as neoadjuvant treatment for ER-positive, HER2-positive early breast cancer Background and study aims This is a study where patients with early breast cancer will be given a combination of medications before they have their operation to remove the breast cancer. We want to look at whether this combination of drugs may be successful as a treatment for early breast cancer. We will be looking at post-menopausal women with early breast cancer that is ER-positive, PgR-positive and HER2-positive, and who are eligible for surgery. Breast cancer that has a significant number of receptors for either oestrogen (ER+) or progesterone (PgR+) is considered hormone-receptor positive and can be treated with either hormone therapy alone or chemotherapy followed by hormone therapy. ER+ breast cancers are routinely treated with hormone therapy that blocks the oestrogen receptor, this type of therapy is more effective when combined with another drug which blocks a molecule called CDK4/6. About 15% of all breast tumours have higher levels of a protein known as HER2, called HER2-positive (HER2+) breast cancers. These cancers tend to grow and spread faster than breast cancers that are HER2-negative, but are much more likely to respond to routine treatment with drugs that target the HER2 protein. 50% of HER2+ breast cancers are also ER+. Research has shown that the combination of HER2 therapy with hormone therapy is more active than hormone therapy alone. Who can participate? Patients aged 18 years and over with early breast cancer that is ER+, PgR+ and HER2+ What does the study involve? Participants receive a combination of treatments: letrozole to block oestrogen receptor (ER), plus trastuzumab and tucatinib to block HER2 and palbociclib to block CDK4/6. What are the possible benefits and risks of participating? The study enables the avoidance of chemotherapy and all its potential side effects and issues while allowing access to a neoadjuvant regimen with agents which have previously shown evidence of clinical activity. The treatment may benefit the patient by reducing the size of their tumour and hence reducing the extent of surgery including breast preservation. The information we get from this study may help us to improve the future treatment of patients with ER+, PgR+ and HER2+ breast cancer. The results from this study will be used to help us improve treatments for postmenopausal women with ER+, PgR+ and HER2+ early breast cancer who require neoadjuvant therapy. Participants will attend additional visits, whether for screening or for treatment that falls outside of standard care. There may be associated costs of travel and availability of time for patients (e.g. taking annual leave). Additional tests and procedures will be required as part of the trial including taking blood at five additional timepoints, two additional research breast biopsies and two additional breast scans. This will be explained in the patient information sheet including the risks of these procedures. Patients may experience adverse events that may be painful, life-threatening or cause death. All possible mitigations have been put in place to protect patients including stringent inclusion and exclusion criteria and patient monitoring. Patients will be informed of possible adverse events and directed to where to find more information in the patient information sheet. Where is the study run from? The University of Liverpool (UK) When is the study starting and how long is it expected to run for? April 2023 to January 2026 Who is funding the study? 1. Seagen (USA) 2. Pfizer (USA; Donation of palbociclib) Who is the main contact? 3-pillars@liverpool.ac.uk, Liverpool Clinical Trials Centre (UK) https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-palbociclib-letrozole-trastuzumab-and-tucatinib-before-surgery-for-breast-cancer The pathological complete response (PCR) rate after completion of study treatment as defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery irrespective of in situ carcinoma in the breast (ypT0/ypTis, ypN0). Measured after 24 weeks of treatment. 1. The difference in the proliferation marker Ki67 (% positive tumour cells) as tested by IHC from baseline to 2 weeks of treatment and from baseline to after 23 weeks of treatment. 2. The objective radiological response rate as defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1, as per Investigator’s assessments by breast USS, mammogram or MRI after completion of study treatment. Measured after 24 weeks of treatment. 3. The objective clinical response rate after 24 weeks of treatment as per tumour overall objective response rate (ORR), defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1 as per Investigator’s assessments by breast USS, mammogram or MRI after completion of study treatment. Measured after 24 weeks of treatment. 4. The proportion of tumours with a Preoperative Endocrine Prognostic Index (PEPI) score of 0 or 1 after completion of study treatment. Measured after 24 weeks of treatment. 5. Safety and tolerability in terms of: 5.1. Defined Grade 1 and 2 toxicities as classified by NCI-CTCAE v5.0 recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.2. Grade 3+ toxicity as classified by NCI-CTCAE v5.0 recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.3. Serious Adverse Events (SAEs) recorded at each visit from start of trial treatment until 4-week post-surgery visit 5.4. Withdrawal from trial treatment due to toxicity recorded at End of Treatment 5.5. Delays to scheduled surgery (due to treatment related toxicities as determined by the investigator) recorded at the Surgery visit Ethics approval required Seasonal REC (Health Research Authority)

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/LO/0388 10.1186/ISRCTN37422164 2021-006077-34 1004806 CPMS: 58079, UoL001650 2021-006077-34 1004806 58079 UoL001650 Single-arm open-label non-randomized study Interventional Non randomised study Treatment 2026-01-31T00:00:00.000Z United Kingdom England Clatterbridge Cancer Centre

65 Pembroke Pl

Liverpool United Kingdom L7 8YA Nottingham University Hospitals NHS Trust - City Campus

Nottingham City Hospital Hucknall Road

Nottingham United Kingdom NG5 1PB RX1CC@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Bristol and Weston NHS Foundation Trust

Bristol Haematology and Oncology Centre University Hospitals Bristol and Weston NHS Foundation Trust Horfield Road

Bristol United Kingdom BS2 8ED Leeds Teaching Hospitals NHS Trust

St. James's University Hospital Beckett Street

Leeds United Kingdom LS9 7TF RR8@2.16.840.1.113883.2.1.3.2.4.18.48 Hull University Teaching Hospitals NHS Trust

Hull Royal Infirmary Anlaby Road

Hull United Kingdom HU3 2JZ RWA@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Patients eligible for the trial must comply with all of the following at registration: 1. 18 years old and greater 2. Newly diagnosed (no previous history of invasive breast cancer) histologically confirmed breast cancer 3. Tumour measuring ≥15 mm in longest diameter by ultrasound (US), mammogram or MRI or any size with axillary lymph node involvement 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 5. Postmenopausal as defined by one of the following criteria: 5.1. Prior bilateral oophorectomy 5.2. Age ≥55 years with an intact uterus and EITHER amenorrhoeic for >12 month OR have recorded Follicle-Stimulating Hormone (FSH) and oestradiol levels within the post-menopausal range within the last 12 months 5.3. Age <55 years with an intact uterus, amenorrhoeic for >12 month AND Follicle-Stimulating Hormone (FSH) and oestradiol levels within the post-menopausal range within the last 12 months 5.4. Women who have had a hysterectomy with intact ovaries with FSH and estradiol levels in the postmenopausal range (as per local reference ranges) 6. ER-positive defined as a Quick Allred Score of ≥6 7. PgR-positive defined as a Quick Allred Score of ≥6 8. HER2-positive defined by immunohistochemistry - 3+ by Herceptest/similar assay or gene amplification as determined by FISH/CISH/D-DISH and the ratio of HER2 to CEP17 probes >2.0 9. Adequate bone marrow function defined by all of the following: 9.1. Haemoglobin (Hb) ≥10 g/dl 9.2. White cell count ≥3.0x10^9 9.3. Absolute Neutrophil Count (ANC) >1.5 x10^9/L 9.4. Platelets ≥100 x10^9/L 10. Adequate renal function defined by a serum creatinine ≤1.5 x Upper Limit of Normal (ULN) (according to local reference ranges) 11. Adequate liver function defined by: 11.1. Total bilirubin ≤1.5 ULN (except for patients with clearly documented Gilbert’s syndrome) 11.2. Alanine transaminase (ALT) or aspartate transaminase (AST) ≤1.5 ULN 11.3. Alkaline phosphatase ≤1.5 ULN 12. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤1.5 X ULN, unless on medication known to alter INR and PTT/aPTT (values within acceptable ranges as per local protocol) 13. Left ventricular ejection fraction (LVEF) of 50% or higher (determined by echocardiography or multiple-gated acquisition scanning) 14. Available paraffin-embedded tumour block taken at diagnostic biopsy for central assessment of Ki67 15. Able to swallow capsules 16. Provided written informed consent Mixed 18 Years Female 90 Any patient meeting any of the criteria listed below will be excluded from study participation: 1. Inflammatory or inoperable breast cancer 2. Evidence of bilateral invasive breast cancer 3. Clinically or radiological evidence of metastatic disease (staging to be done in accordance with local guideline) 4. Concomitant use (defined as use within 12 weeks prior to entry) of Hormone Replacement Therapy (HRT) or any other oestrogen-containing medication or supplementation 5. Any prior treatment with any CDK 4/6 inhibitor 6. Use of a strong CYP3A4 or CYP2C8 inhibitor, or food or drugs that are known CYP3A4 inhibitors, within 2 weeks of starting study treatment and during study (See Appendix 3) 7. Use of a strong CYP3A4 or CYP2C8 inducer, or drugs known to be CYP3A4 inducers, within 5 days of starting study treatment and during study (See Appendix 2 and Appendix 3) 8. No plan to commence treatment with CYP3A substrates within 2 weeks of starting study treatment and during study (See Appendix 1) 9. Any prior treatment with HER2-directed therapy 10. Previous investigational medicinal products for any condition within 4 weeks of registration date 11. Any prior history of invasive malignancy within 5 years of starting treatment where there is a medium or high risk of reoccurrence (other than treated basal cell carcinoma or squamous cell carcinoma of the skin and cervical carcinoma in situ or cancers treated with surgery alone). 12. QTc >480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP) 13. Significant cardiovascular disease including but not limited to: 13.1. History of documented congestive cardiac failure 13.2. Angina pectoris requiring anti-anginal medication 13.3. Evidence of transmural infarction on ECG 13.4. Poorly controlled hypertension or uncontrolled asymptomatic hypertension as determined by the investigator 13.5. Clinically significant valvular heart disease 13.6. Ventricular significant arrhythmia requiring therapy 13.7. High-risk uncontrolled arrhythmias or sudden cardiac arrest 14. Has significant gastro-intestinal disease including but not limited to active inflammatory bowel disease, chronic diarrhoea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection which would preclude the adequate oral absorption of medications. 15. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia) 16. Evidence of bleeding diathesis 17. Active bacterial infection (as defined by the use of oral or IV antibiotics at the time of study registration or systemic fungal infection 18. Known human immunodeficiency virus (HIV) positivity (screening HIV is not required for study enrolment) 19. Known active or inactive hepatitis carrier, for example, hepatitis B surface antigen (HBsAg) positive (screening hepatitis B or C is not required for study enrolment) 20. Recent vaccination with a live virus defined as within 28 days of study registration 21. Known hypersensitivity to letrozole, palbociclib, trastuzumab or tucatinib, or to any of the excipients. 2024-08-29T00:00:00.000Z 2026-03-01T00:00:00.000Z ER-positive, PgR-positive and HER2-positive early breast cancer Cancer 3-Pillars is a single-arm trial so participants will not be randomised. All participants taking part in the 3-Pillars trial will receive the same treatment as follows: 1. Tucatinib (300mg tablet taken orally twice daily for 24 weeks or until surgery) 2. Palbociclib (75mg/day on a 28 day schedule of 21 days on and 7 days off for a total of 24 weeks) 3. Letrozole (2.5mg tablet taken orally once daily for 24 weeks or until surgery) 4. Trastuzumab (600mg subcutaneous injection every 3 weeks for 24 weeks or until surgery) Dose reductions are permissible for tucatinib as follows: 1. Tucatinib – 300mg starting dose, 250mg first dose reduction, 200mg second dose reduction, 150mg third dose reduction 2. Palbociclib – no dose reduction 3. Letrozole – no dose reduction 4. Trastuzumab – no dose reduction No dose reductions are permissible for palbociclib, letrozole and trastuzumab. Participants will receive a 4-week post-surgery follow-up for a translational blood sample and adverse event recording. Drug Phase II Tucatinib, palbociclib, letrozole, trastuzumab The datasets generated during and/or analysed during the current study are/will be available upon request from Liverpool Clinical Trials Centre, LCTC@liverpool.ac.uk. At the end of the trial, after the primary results have been published, the anonymised individual participant data (IPD) and associated documentation (e.g. protocol, statistical analysis plan, annotated blank CRF) will be prepared in order to be shared with external researchers. Patient identifiable data will only be shared with external researchers if the participants have consented to this onward disclosure in accordance with the Common Law Duty of Confidentiality, or if the external researchers obtain approval to waive this Common Law requirement (i.e. Section 251 Approval via the Confidentiality Advisory Group (CAG) / approval from the Public Benefit & Privacy Panel for Health & Social Care (PBPP)) or if the IPD has been fully anonymised prior to sharing. All requests for access to the IPD will be assessed by the Sponsor and must be agreed upon by all Data Controller organisations. Available on request

Adult PISC

3e8f57ff-0eeb-4aa7-8620-0db4e0e44d43 e5644359-6220-458f-b80d-658e365b928c 54b4306b-cb48-4788-a8b4-55579e8a683b 3029cb28-279f-4490-b441-0c5c157541c2 74130d5e-5e82-40f4-9664-2930859a4aeb Yes Participant information sheet 43448 _PIS_v1.0_21November2022.pdf e37fb45c-c28d-487c-9c65-a0b66920d0e8 true application/pdf 140773 daf4e0429d9a8b8cff00373a478d97aa Adult PISC 43448_Adult PIS_v1.0_06February2023.pdf d2e22f98-1990-412c-8d27-606df2e9e1af true application/pdf 479968 3e5f5985f9021fa3c87f36a73cb48f6c Participant information sheet ISRCTN37422164 3-PILLARS_Adult PISC_ V3.0 28Mar2024 clean.pdf 201af083-5730-49f3-87e5-893d0336632c true application/pdf 475404 1798b6877745b6ff3bf445187b1863cf Carlo Palmieri https://orcid.org/0000-0001-9496-2718 Principal investigator

University of Liverpool Department of Molecular and Clinical Cancer Medicine Biosciences Building Crown Street

Liverpool United Kingdom L69 7BE +44 (0)151 7949813 C.Palmieri@liverpool.ac.uk Public Carlo Palmieri Scientific

University of Liverpool Department of Molecular and Clinical Cancer Medicine Biosciences Building Crown Street

Liverpool United Kingdom L69 7BE +44 (0)151 7949813 C.Palmieri@liverpool.ac.uk Public Liverpool Clinical Trials Centre Public

Waterhouse Building Bloc C 1-5 Brownlow Street

Liverpool United Kingdom L69 3GL None provided 3-pillars@liverpool.ac.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial Pfizer http://dx.doi.org/10.13039/100004319 17435333 true An adaptive-design randomised placebo-controlled trial of baclofen in the treatment of alcohol use disorder in patients with liver cirrhosis BASIS trial The primary objective is to investigate the effect of baclofen compared with placebo in the treatment of Alcohol Use Disorder (AUD) in patients with alcohol-related cirrhosis. Secondary objectives: 1. To determine if the treatment of AUD with baclofen in patients with alcohol-related cirrhosis is superior to placebo 2. To determine which dose(s) of baclofen is/are most effective in improving AUD treatment outcomes in patients with alcohol-related cirrhosis in comparison to placebo 3. To assess the relationship between variability in baclofen exposure and efficacy and safety parameters. 4. To monitor and compare the safety profile of the baclofen arms, including dose dependency, in comparison to the placebo arm Background and study aims Continued alcohol consumption in people diagnosed with cirrhosis quickens the time to death. It follows, that helping people stop drinking (abstinence) can lead to improvements in how the liver works, resulting in longer life expectancy. Baclofen has been identified as a promising alcohol anti-craving medicine with potential to help people to stop drinking which is clearly the most important aim of treatment. What does the study involve? Our proposed trial will evaluate whether baclofen is an effective treatment option in patients with alcohol-related liver cirrhosis, and which dose(s) is/are safe and effective. This trial will test 3 different doses of baclofen and a placebo (dummy treatment) in patients with alcohol-related cirrhosis over 24 weeks. Participants will be recruited from secondary care settings within NHS trusts with the trial population reflecting the range of disease severity, co-morbidities (co-existing disease), and social and ethnic groups encountered in everyday clinical practice. The patients will be aged 18-75 years. All participants will undergo screening to detect suicidal ideation using the C-SSRS Screen between day 7 and day 10 post registration. This will ensure time for patients to receive appropriate medical treatment and reduce test anxiety. An answer of 'yes' to questions 3, 4, 5, or 6 will result in referral for mental health assessment following local standard of care procedures. At the randomisation visit, results of mental health assessment will determine eligibility (i.e. patient determined to be at risk of suicide will not be eligible for the trial). After two weeks, all participants will be assessed for entry to randomisation Participants who do not meet the entry criteria will not be randomised. Participants will be randomised after the run-in period to one of the four treatment arms using double-blind methods, meaning neither the participants or the research doctors and nurses will know which treatment has been allocated. We will also undertake blood sampling to determine the relationship between the amount of baclofen in the bloodstream to and how participants respond. This will help us to identify the best dose for each individual. What are the possible benefits and risks of participating? Benefits: Alcohol consumption in the presence of liver cirrhosis leads to poorer patient outcomes in comparison to patients who remain abstinent. Currently there are limited options to promote abstinence in this patient group. Continued alcohol intake increases the risk of advanced liver failure and reduces both short and long‐term survival. The predicted rates of death for patients with alcohol-related cirrhosis is very poor, with mortality rates of 71% at 5 years and 91% at 15 years for patients who continue to drink. Importantly, abstinence is associated with a ~40% reduced risk of mortality from 18 months onwards. Death from alcohol-related cirrhosis usually occurs in people of working age. Also, despite shorter life expectancy, patients admitted with alcohol-related cirrhosis incur substantial costs for healthcare systems. Risks: Baclofen has a well-established safety profile, with known adverse effects documented. Furthermore, the doses to be used have been taken from evidence from trials, and the upper limit of baclofen dosing in the UK (100 mg/day). Specific exclusion criteria have been adopted to minimise the risk of serious adverse events . In addition, suicide and suicide-related events have been reported in patients treated with baclofen. In most cases, the patients had additional risk factors associated with an increased risk of suicide including alcohol use disorder. The requirement for abstinence prior to recruitment will help reduce this risk. Patients with a recent suicide attempt or a history of previous multiple suicide or self-harm episodes will be excluded as will patients exhibiting suicidal ideation at the time of planned recruitment. During the run in period participants will undergo screening to detect suicidal ideation to determine if they need to be referred for mental health assessment. Following the mental health assessment, if the participant is assessed as being at risk of suicide they will not be eligible for the trial. The common side effects of baclofen include dizziness, weakness, confusion, headache, nausea, constipation, difficulty falling asleep or staying asleep, tiredness, frequent urination. Where is the study run from? Liverpool University Hospitals NHS Foundation Trust is the Sponsor of this study and is responsible for managing it. They are based in United Kingdom. They have asked that the day-to-day running of the study is carried out by a team based at the Liverpool Clinical Trials Centre, UK (LCTC, part of the University of Liverpool). A separate team from the University of Liverpool is responsible for managing the sub-study blood samples. When is the study starting and how long is it expected to run for? November 2022 to March 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (UK). Who is the main contact? basis@liverpool.ac.uk Continued abstinence post randomisation for 24 weeks measured using Timeline Followback Current secondary outcome measures as of 16/06/2025: At baseline and weeks 4, 8, 16 and 24 of follow-up unless noted otherwise: 1. Self-reported alcohol consumption since previous visit via Timeline Followback to measure: 1.1. Average units per drinking day 1.2. Percent days abstinent. 1.3. Number of heavy drinking days. 2. Changes in alcohol usage and dependency questionnaires (AUDIT, SADQ, APQ). SADQ to be completed at baseline and if required at follow up, when triggered by Timeline Followback and participant is drinking again. 3. Time to lapse (time to first alcoholic drink) measured using Timeline Followback. 4. Time to relapse (defined as time to consumption of ≥5 units for women, ≥6 units for men in a single day) measured using Timeline Followback. 5. Biological markers of alcohol consumption and liver function measured by: 5.1. Ethyl glucuronide test in urine using dipstick at baseline, weeks 1, 2, 4, 8, 16 and 24 of follow-up 5.2. Breath alcohol at baseline, weeks 1, 2, 4, 8, 16 and 24 of follow-up 5.3. LFTs at baseline, weeks 4, 8, 16 and 24 of follow-up 6. Delta changes in liver function as per Child-Pugh and Model of End Stage Liver Disease (MELD-Na) 7. Alcohol craving by Penn Alcohol Craving Scale (PACS) 8. Subsequent hospital attendances and admissions (including unplanned use) at weeks 4, 8, 16 and 24 of follow-up 9. Rate of survival at time of data analysis using median duration of follow-up, ONS data clarification that death data may be requested at the final analysis if required 10. Medication adherence (pill count) at weeks 1, 2, 4, 8, 16 and 24 of follow-up 11. Blood sampling to determine a population pharmacokinetic model for baclofen in patients with alcohol-related liver cirrhosis 12. Recording and assessment of related adverse events at baseline and weeks 1, 2, 4, 8, 16 and 24 of follow-up Previous secondary outcome measures: At baseline and weeks 4, 8, 16 and 24 of follow-up unless noted otherwise: 1. Self-reported alcohol consumption since previous visit via Timeline Followback to measure: 1.1. Average units per drinking day 1.2. Percent days abstinent. 1.3. Number of heavy drinking days. 2. Changes in alcohol usage and dependency questionnaires (AUDIT, SADQ, APQ). SADQ to be completed at baseline and if required at follow up, when triggered by Timeline Followback and participant is drinking again. 3. Quantity and Frequency of alcohol consumption measured using Timeline Followback. 4. Time to relapse (time to first alcoholic drink) measured using Timeline Followback. 5. Time to relapse (defined as time to consumption of ≥5 units for women, ≥6 units for men in a single day) measured using Timeline Followback. 6. Biological markers of alcohol consumption and liver function measured by: 6.1. Urine Ethyl glucuronide (optional; measured in around 25% of participants) at weeks 4, 8, 16 and 24 of follow-up, where optional consent has been provided 6.2. Breath alcohol at baseline, weeks 1, 2, 4, 8, 16 and 24 of follow-up 6.3. LFTs at baseline, weeks 1, 2, 4, 8, 16 and 24 of follow-up 7. Delta changes in liver function as per Child-Pugh and Model of End Stage Liver Disease (MELD-Na) 8. Alcohol craving by Penn Alcohol Craving Scale (PACS) 9. Subsequent hospital attendances and admissions (including unplanned use) at weeks 4, 8, 16 and 24 of follow-up 10. Rate of survival at time of data analysis using median duration of follow-up, ONS data clarification that death data may be requested at the final analysis if required 11. Medication adherence (pill count) at weeks 1, 2, 4, 8, 16 and 24 of follow-up 12. Blood sampling to determine a population pharmacokinetic model for baclofen in patients with alcohol-related liver cirrhosis 13. Recording and assessment of related adverse events at baseline and weeks 1, 2, 4, 8, 16 and 24 of follow-up Ethics approval required South Central – Berkshire B Research Ethics Committee

Whitefriars, Level 3, Block B, Lewins Mead

Bristol United Kingdom BS1 2NT 23/SC/0006 10.1186/ISRCTN17435333 2022-000154-28 1006141 CPMS: 54363, R&I 6040 2022-000154-28 1006141 54363 R&I 6040 Interventional double-blind randomized parallel-group placebo-controlled trial Interventional Randomised parallel trial Treatment 2027-03-31T00:00:00.000Z United Kingdom England Scotland Royal Liverpool University Hospital

Prescot Street

Liverpool United Kingdom L7 8XP St Mary's Hospital

Imperial College Healthcare NHS Trust South Wharf Road

London United Kingdom W2 1BL Glasgow Royal Infirmary

84 Castle Street

Glasgow United Kingdom G4 0SF Royal Free Hospital

Pond Street

London United Kingdom NW3 2QG Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge United Kingdom CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 Kings College Hospital

Mapother House De Crespigny Park Denmark Hill

London United Kingdom SE5 8AB NV178@2.16.840.1.113883.2.1.3.2.4.18.48 Freeman Road Hospital

Freeman Road High Heaton

Newcastle upon Tyne United Kingdom NE7 7DN RTR52@2.16.840.1.113883.2.1.3.2.4.18.48 Aintree Hospitals - Opd

Fazakerley Hospital Lower Lane

Liverpool United Kingdom L9 7AL RET25@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current participant inclusion criteria as of 16/06/2025: At Registration: 1. Age 18 to 75 years 2. Confirmed diagnosis of alcohol-related cirrhosis classified according to the Child-Pugh classification 3. Abstinent from alcohol at the time of registration for between ≥1 day and <42 days 4. Capacity to provide informed consent At Randomisation: 1. Age 18 to 75 years 2. Confirmed diagnosis of alcohol-related cirrhosis classified according to the Child-Pugh classification 3. Abstinent from alcohol at the time of the baseline/randomisation visit for between ≥14 days and <56 days 4. Capacity to provide informed consent 5. Women of reproductive potential must have a negative pregnancy test at randomisation and use highly effective contraception for the duration of the treatment period Previous participant inclusion criteria: At Registration: 1. Age 18 to 65 years 2. Confirmed diagnosis of alcohol-related cirrhosis classified according to the Child-Pugh classification 3. Abstinent from alcohol at the time of registration for between ≥1 day and <42 days 4. Capacity to provide informed consent At Randomisation: 1. Age 18 to 65 years 2. Confirmed diagnosis of alcohol-related cirrhosis classified according to the Child-Pugh classification 3. Abstinent from alcohol at the time of the baseline/randomisation visit for between ≥14 days and <56 days 4. Capacity to provide informed consent 5. Women of reproductive potential must have a negative pregnancy test at randomisation and use highly effective contraception for the duration of the treatment period Adult 18 Years 75 Years All 400 At registration: 1. Planning to become pregnant, is pregnant or breastfeeding 2. Overt hepatic encephalopathy or trans-jugular intrahepatic porto-systemic shunt in situ 3. Severe renal impairment (stage 5 chronic kidney disease and/or current haemodialysis) 4. History of illicit drug use excluding marijuana in the previous 4 weeks 5. Concurrent use of opioid substitution therapy 6. Use of licenced alcohol anti-craving pharmacotherapy (such as acamprosate, disulfiram naltrexone, nalmefene) in previous 12 weeks 7. Use of baclofen for any purpose in previous 12 weeks 8. Peptic ulceration detected by endoscopy within 14 days of registration. 9. Known hypersensitivity to baclofen or structurally related drugs or any other component of the formulation. 10. Poorly controlled major psychiatric disorder such as schizophrenia or bipolar disorder 11. Individuals who have participated in a trial of a medicinal product within 12 weeks preceding registration 12. Poorly controlled epilepsy 13. Rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption 14. Suffering from porphyria At randomisation: 1. Planning to become pregnant, is pregnant or breastfeeding 2. Overt hepatic encephalopathy or trans-jugular intrahepatic porto-systemic shunt in situ 3. Severe renal impairment (stage 5 chronic kidney disease and/or current haemodialysis) 4. History of illicit drug use excluding marijuana in the previous 6 weeks 5. Concurrent use of opioid substitution therapy, or use in the previous 14 days 6. Use of licenced alcohol anti-craving pharmacotherapy (such as acamprosate, disulfiram naltrexone, nalmefene) in previous 14 weeks 7. Use of baclofen for any purpose in previous 14 weeks 8. Peptic ulceration detected by endoscopy within 28 days of the baseline/randomisation visit. 9. Known hypersensitivity to baclofen or structurally related drugs or any other component of the formulation 10. Scored 3 or more on the C-SSRS Screen and has been assessed by an appropriately qualified mental health practitioner as having suicidal ideation or behaviour prior to the baseline/randomisation visit 11. Poorly controlled major psychiatric disorder such as schizophrenia or bipolar disorder 12. Individuals who have participated in a trial of a medicinal product within 14 weeks preceding the baseline/ randomisation visit 13. Poorly controlled epilepsy 14. Rare hereditary problems of galactose intolerance, total lactose deficiency or glucosegalactose malabsorption 15. Suffering from porphyria 2024-03-18T00:00:00.000Z 2026-03-31T00:00:00.000Z Alcohol use disorder in patients with liver cirrhosis Mental and Behavioural Disorders Current interventions as of 16/06/2025: All participants will undergo screening to detect suicidal ideation using the C-SSRS Screen between day 7 and day 10 post registration. This will ensure time for patients to receive appropriate medical treatment and reduce test anxiety. An answer of 'yes' to questions 3, 4, 5, or 6 will result in referral for mental health assessment following local standard of care procedures. At the randomisation visit, results of mental health assessment will determine eligibility (i.e. patient determined to be at risk of suicide will not be eligible for the trial). After two weeks, all participants will be assessed for entry to randomisation. Participants who do not meet the entry criteria will not be randomised Registered participants will be required to abstain from alcohol for 2 weeks prior to randomisation. Following the two weeks run-in period, eligible participants will be randomised via a secure (24 hour) web-based randomisation system. Participants will be randomised to either one of three doses of baclofen or a matching placebo (in a ratio of 1:1:1:1). Participants will be instructed to take one tablet orally three times per day (TDS). The study arms are: • baclofen 10 mg TDS (max daily dose 30 mg) • baclofen 20 mg TDS (max daily dose 60 mg) • baclofen 30 mg TDS (max daily dose 90 mg) • placebo TDS Participants will be prescribed tablets at baseline and weeks 1, 2, 4, 8, 16 and 24. Blinded treatment packs will be administered at baseline and weeks 1, 2, 4, 8, 16 and 24, with all participants attending titration visits at week 1 and week 2. Participants will be titrated up to the next dose level if this is in accordance with their randomised dose allocation. Participants randomised to 20 mg TDS will be initially be given 10 mg TDS for the first week, then increasing to 20 mg TDS for the remainder of the treatment period. Participants randomised to 30 mg TDS will initially be given 10 mg TDS for the first week, then 20 mg TDS for the second week increasing to 30 mg TDS for the rest of the treatment period. When end of treatment is reached participants will be unblinded and a phased reduction in baclofen dose applied for those in the active arms. The protocol provides a down-titration regime; however, this can be adjusted for the individual needs of each participant. Down titration medication will be sourced via usual NHS supply arrangements. Previous interventions: All participants will undergo screening to detect suicidal ideation using the C-SSRS Screen between day 7 and day 10 post registration. This will ensure time for patients to receive appropriate medical treatment and reduce test anxiety. A score of 3 or more will result in referral for mental health assessment following local standard of care procedures. At the randomisation visit, results of mental health assessment will determine eligibility (i.e. patient determined to be at risk of suicide will not be eligible for the trial). After two weeks, all participants will be assessed for entry to randomisation. Participants who do not meet the entry criteria will not be randomised Registered participants will be required to abstain from alcohol for 2 weeks prior to randomisation. Following the two weeks run-in period, eligible participants will be randomised via a secure (24 hour) web-based randomisation system. Participants will be randomised to either one of three doses of baclofen or a matching placebo (in a ratio of 1:1:1:1). Participants will be instructed to take one tablet orally three times per day (TDS). The study arms are: • baclofen 10 mg TDS (max daily dose 30 mg) • baclofen 20 mg TDS (max daily dose 60 mg) • baclofen 30 mg TDS (max daily dose 90 mg) • placebo TDS Participants will be prescribed tablets at baseline and weeks 1, 2, 4, 8, 16 and 24. Blinded treatment packs will be administered at baseline and weeks 1, 2, 4, 8, 16 and 24, with all participants attending titration visits at week 1 and week 2. Participants will be titrated up to the next dose level if this is in accordance with their randomised dose allocation. Participants randomised to 20 mg TDS will be initially be given 10 mg TDS for the first week, then increasing to 20 mg TDS for the remainder of the treatment period. Participants randomised to 30 mg TDS will initially be given 10 mg TDS for the first week, then 20 mg TDS for the second week increasing to 30 mg TDS for the rest of the treatment period. When end of treatment is reached participants will be unblinded and a phased reduction in baclofen dose applied for those in the active arms. The table provided in the email illustrates a down-titration regime; however, this can be adjusted for the individual needs of each participant. Down titration medication will be sourced via usual NHS supply arrangements. Drug Phase III Baclofen Anonymous data from the trial will be made available to share with external researchers. All requests for access to these data will be reviewed by the sponsor and data controllers Available on request

Study website Migrated from study website field

89540ceb-a733-4299-b0d4-c2e21cf8ec9a 15f975eb-aedc-4880-9f33-66c13454dee2 5be7bfd4-9f1a-4e0f-b7f6-6209302692e0 bbee2e4e-438e-4fb6-bf56-7168bb0454b9 Yes Paul Richardson Principal investigator

Royal Liverpool University Hospital NHS FT Prescot Street

Liverpool United Kingdom L7 8XP +44 151 706 3568 basis@liverpool.ac.uk Public BASIS Trial Team Public

Liverpool Clinical Trials Centre (LCTC) Block C Waterhouse Building 3 Brownlow Street

Liverpool United Kingdom L69 3GL - basis@liverpool.ac.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 54174557 true Steroid Treatment Trial in JIA (STAR-JIA): A randomised trial to compare the effectiveness, safety and cost-effectiveness of intravenous versus oral corticosteroid induction regimens for children and young people with juvenile idiopathic arthritis STAR-JIA Primary objectives: To compare the clinical effectiveness of intravenous methylprednisolone versus oral prednisolone for controlling new-onset polyarticular juvenile idiopathic arthritis (JIA) in JIA Core Outcomes. Secondary objectives: 1. To compare the differences in JIA Core Outcomes for intravenous methylprednisolone versus oral prednisolone for the following domains: 1.1. Pain 1.2. Function 1.3. Health-related Quality of Life (HRQOL) 2. To assess the effectiveness of intravenous versus oral corticosteroids in minimising the need for additional treatments including all corticosteroid routes and additional disease-modifying anti-rheumatic drugs (DMARDs)/biologics. 3. To evaluate short/medium-term safety and tolerability of IV versus oral corticosteroids, with regards to adverse reactions, serious adverse events, laboratory assessments and paediatric glucocorticoid toxicity index (pGTI). 4. To determine if a dose-response relationship can be identified in the efficacy/adverse responses to corticosteroids across all participants by secondary analysis, normalising corticosteroids received for dose, bioavailability and potency using previously published data. Background and study aims The aim of this study is to compare two different steroid treatments in children and young people with new-onset polyarticular juvenile idiopathic arthritis (JIA) to find out which is best. Medications used in the long-term management of JIA take around 12 weeks to start working. Steroids act quickly, reducing inflammation whilst the other medications start to work but have many potential side effects. There is a lack of evidence to suggest whether intravenous steroids or oral steroids are more effective, safe, tolerable for patients and which have a greater impact on quality of life. Who can participate? Patients aged 1-18 years of age with at least five inflamed joints and newly diagnosed polyarticular JIA What does the study involve? They will be randomly allocated to either a 6-week course (reducing dose regimen) of prednisolone liquid or tablets, taken at home OR a 3-day course of intravenous methylprednisolone on a hospital day-case unit. Participants will be assessed before starting treatment (baseline) and four follow-up visits at 6, 12, 24 and 52 weeks, in line with standard care appointments. Study visits will include assessments in standard care however, additional study-specific assessments will include reporting of side effects, and steroid toxicity risk including extra blood tests, questionnaires relating to the impact of JIA and treatment on quality of life and cost. The study offers an option for participants to donate blood samples for storage in a biobank for future research. Samples will not be analysed as part of the study but adopted by Liverpool University Biobank. What are the possible benefits and risks of participating? The direct burden on participation will be minimal as all research visits have been scheduled at the same time as standard-of-care visits to minimise the burden to participants. Research blood samples are taken at the same time as standard-of-care bloods to reduce burden. Participants will be asked to complete several questionnaires which will prolong their clinic appointments. Once complete the questionnaire will be handed to the research team. Risks associated with being treated with steroids (the IMP and the comparator) via different routes for JIA with the IMP, These risks are stated in the trial information sheets and site teams are appropriately trained as both routes of administration are used as standard of care. All of the above risks are minimized with appropriate training and following policies and procedures by hospital Trusts and as stated in the protocol. For participants receiving oral prednisolone from hospital pharmacies, the pharmacy will dispense the drug as prescribed with appropriate guidance for taking it. For participants receiving IV methylprednisolone over 3 days on a hospital day unit, nurses who normally work on the day unit and have been appropriately trained to give IV methylprednisolone will be responsible for administering the drug and monitoring participants. It will not be given by Research Nurses who may be less familiar with the administration of this drug and do not usually administer this drug. This will minimize the risk of drug preparation, administration and monitoring errors. Where is the study run from? Alder Hey Children's NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? July 2023 to July 2028 Who is funding the study? Health Technology Assessment Programme (UK) Who is the main contact? star-jia@liverpool.ac.uk Primary clinical outcome: Disease activity measured using the JADAS10 score at 0 weeks (Baseline) and 6 weeks Primary economic outcomes: 1. Incremental cost per quality-adjusted life year (QALY) gained measured using Resource Use Questionnaires and Patient Level Information and Costing System (PLICS) data at 0 weeks (Baseline), 6 weeks, 12 weeks, 24 weeks and 52 weeks. 2. Resource use, costs and health utilities associated with IV and oral corticosteroids measured using Resource Use Questionnaires and Patient Level Information and Costing System (PLICS) data at 0 weeks (Baseline), 6 weeks, 12 weeks, 24 weeks and 52 weeks. 1. Disease activity in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured using the American College of Rheumatology (ACR) Pediatric Response Criteria (30, 50, 70, 90, 100) at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 2. Disease activity in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA), randomised to IV methylprednisolone or oral prednisolone measured using the JADAS (10,27,71) at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 3. Disease activity in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured by JADAS10 cut-off scores at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 4. Pain in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured using the Pain Visual Analogue Scale (Pain VAS) at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 5. Function in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured using the Childhood Health Assessment Questionnaire (CHAQ) at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 6. Health-related Quality of Life (HRQoL) in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured using Child Health Utility 9D Questionnaire (CHU-9D) and CAPTURE-JIA PROM at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks. 7. Requirement for additional treatment for subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) due to failure to respond to IV methylprednisolone or oral prednisolone measured using concomitant medications recorded at 6 weeks, 12 weeks, 24 weeks, 52 weeks. 8. Glucocorticoid toxicity in subjects with polyarticular Juvenile Idiopathic Arthritis (JIA) randomised to IV methylprednisolone or oral prednisolone measured using Paediatric Glucocorticoid Toxicity Index (pGTI) scores at 0 weeks (baseline), 6 weeks, 12 weeks, 24 weeks, 52 weeks Ethics approval required Yorkshire and the Humber - Leeds East

NHSBT Newcastle Blood Donor Centre, Holland Drive

Newcastle-upon-Tyne United Kingdom NE2 4NQ 23/YH/0173 10.1186/ISRCTN54174557 1007610 CPMS: 58347, AH23-05-006 1007610 58347 AH23-05-006 Open randomized controlled parallel-group trial Interventional Randomised controlled trial Efficacy Safety Treatment 2028-07-31T00:00:00.000Z United Kingdom England Northern Ireland Wales Alder Hey Hospital

Eaton Road West Derby

Liverpool England L12 2AP 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 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 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 Noahs Ark Childrens Hospital for Wales

Cardiff & Vale University Health Bd Heath Park

Cardiff Wales CF14 4XW 7A4H1@2.16.840.1.113883.2.1.3.2.4.18.48 John Radcliffe Hospital

Headley Way Headington

Oxford England OX3 9DU RHW12@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Preston Hospital

Sharoe Green Lane Fulwood

Preston England PR2 9HT R0A87@2.16.840.1.113883.2.1.3.2.4.18.48 Norfolk and Norwich Hospital

Colney Lane Colney

Norwich England NR4 7UY RGT1L@2.16.840.1.113883.2.1.3.2.4.18.48 Freeman Road Hospital

Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTR52@2.16.840.1.113883.2.1.3.2.4.18.48 New Cross Hospital

Wolverhampton Road Heath Town

Wolverhampton England WV10 0QP RL403@2.16.840.1.113883.2.1.3.2.4.18.48 Bradford Royal Infirmary

Chesnut House Duckworth Lane

Bradford England BD9 6RJ RR842@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Stoke University Hospital

Newcastle Road

Stoke-on-trent England ST4 6QG RJE01@2.16.840.1.113883.2.1.3.2.4.18.48 Manchester Royal Infirmary

Oxford Road

Manchester England M13 9WL RM326@2.16.840.1.113883.2.1.3.2.4.18.48 Great Ormond Street Hospital for Children

Great Ormond Street

London England WC1N 3JH RAJ2E@2.16.840.1.113883.2.1.3.2.4.18.48 Northern General Hospital

Northern General Hospital NHS Trust C Floor, Huntsmnan Building Herries Road

Sheffield England S5 7AU NTPP8@2.16.840.1.113883.2.1.3.2.4.18.48 Addenbrooke's Hospital

Hills Road

Cambridge England CB2 0QQ Cheltenham General Hospital

Sandford Road

Cheltenham England GL53 7AN 691C0@2.16.840.1.113883.2.1.3.2.4.18.48 Queens Medical Centre

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH RTG09@2.16.840.1.113883.2.1.3.2.4.18.48 Guy's and St Thomas' NHS Foundation Trust

St Thomas' Hospital Westminster Bridge Road

London England SE1 7EH RJ1@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 Patient 1. Participants must be between 1-18 years of age inclusive 2. New onset pcJIA diagnosed by a paediatric rheumatologist (to include polyarticular rheumatoid factor (RF+) positive, polyarticular RF negative, enthesitis-related arthritis, psoriatic arthritis and extended oligo-articular). This includes new diagnosis of JIA with at least 5 joints affected and patients previously categorised as oligoarticular JIA (with 4 joints or less) who have extended to at least 5 joints. 3. Participants are expected to be able to commence allocated treatment within 1 week of randomisation 4. Written, informed consent and where appropriate, assent obtained from participant or their legal representative 5. Participants of child-bearing potential must be willing to abstain from sexual intercourse from consent to their final visit and/or use another acceptable contraception method as described in section 9.10.5 of this protocol Mixed 1 Year 18 Years All 130 0 1. Any contraindication to starting corticosteroids 2. Any contraindication to starting methotrexate 3. Pregnancy 4. Treatment with systemic corticosteroids within 4 weeks preceding screening (includes IV, IA, IM and oral) 5. Treatment with methotrexate within 12 weeks preceding screening 6. Any co-morbidity which in view of the treating clinician makes participation inappropriate 2024-03-05T00:00:00.000Z 2027-02-06T00:00:00.000Z Juvenile idiopathic arthritis (polyarticular) Musculoskeletal Diseases IMP: Intravenous methylprednisolone administered over 3 days on a hospital day unit Comparator: Oral prednisolone taken/administered over 6 weeks at home The doses, frequency and method of administration of the IMP and comparator drug are provided below. IMP: Methylprednisolone Route: Intravenous administration Form: Powder for injection to be prepared for intravenous administration 30 mg/kg per day for 3 consecutive days (Maximum dose: 1g per day) Comparator: Prednisolone Route: Oral administration Form: Tablet or solution The initial dose of prednisolone will be 1 mg/kg per day with a maximum dose of 40 mg. For participants weighing ≥40 kg, the weaning will be a reduction in line with the percentage decrease used for lighter patients. Week of oral prednisolone 1: Dose (patient <40 kg): 1 mg/kg per day; Dose (patient ≥40 kg): 40 mg Week of oral prednisolone 2: Dose (patient <40 kg): 0.75 mg/kg per day; Dose (patient ≥40 kg): 30 mg Week of oral prednisolone 3: Dose (patient <40 kg): 0.5 mg/kg per day; Dose (patient ≥40 kg): 20 mg Week of oral prednisolone 4: Dose (patient <40 kg): 0.375 mg/kg per day; Dose (patient ≥40 kg): 15 mg Week of oral prednisolone 5: Dose (patient <40 kg): 0.25 mg/kg per day; Dose (patient ≥40 kg): 10 mg Week of oral prednisolone 6: Dose (patient <40 kg): 0.125 mg/kg per day; Dose (patient ≥40 kg): 5 mg Drug Phase IV Methylprednisolone, prednisolone The datasets generated during and/or analysed during the current study will be made available on request from Liverpool Clinical Trials Centre, star-jia@liverpool.ac.uk. Available on request

Study website Migrated from study website field

9da9e65c-2b3f-4d05-b8e6-088130e8f5a0 2fb7b1ca-50dc-4d36-acf8-914e4a8a9d42 5dffb1d8-05d3-456a-9826-902b0fffba11 d91be422-263f-40b4-8750-cf24b0ee5b28 Yes Laura Whitty https://orcid.org/0000-0003-3114-0877 Scientific Public

Liverpool Clinical Trials Centre Block C Waterhouse Building Brownlow Street

Liverpool United Kingdom L69 3GL +44 (0)151 7940619 star-jia@liverpool.ac.uk Public Clare Pain Principal investigator

Eaton Road

Liverpool United Kingdom L12 2AP +44 (0)151 2284811 Clare.Pain@alderhey.nhs.uk Public Alder Hey Children's NHS Foundation Trust Hospital/treatment centre https://ror.org/00p18zw56 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 14643179 true Circulating tumour DNA guided Adaptive BRAF and MEK Inhibitor therapy DyNAMIc Current study objectives as of 01/10/2025: Adaptive therapy relies on the competition between drug-sensitive and drug-resistant subclones to control overall tumour growth. It aims to stabilise tumour burden by allowing a significant population of treatment-sensitive cells to survive, which suppresses the proliferation of the less fit, resistant populations. 1. Patients will have circulating tumour DNA (ctDNA) response upon re-introduction of encorafenib plus binimetinib following the first drug holiday. 2. Encorafenib plus binimetinib therapy using adaptive scheduling based on ctDNA level will improve the time to progression, reduce toxicity and enhance quality of life compared to continuous dosing in patients with stage III unresectable or stage IV melanoma. Objectives: To assess whether tumours respond to the re-introduction of encorafenib plus binimetinib following the first period of stopping the drugs. The researchers will do this by measuring the amount of circulating tumour DNA (ctDNA) in the plasma we obtained from the patients' blood samples, which are taken every 2 weeks. Using data from the main objective, they intend to develop a guideline based on the ctDNA levels, to inform doctors when the adaptive treatment should stop and re-start. The researchers compare the ctDNA results from the two arms to identify the average time it takes for participants to respond to the treatment, how long they may remain stable for, or for the disease to worsen. The time it may take for participants' cancer to worsen (known as progression), will be measured at 6, 12 and 15 months from commencing treatment. Also, the median time to the death of participants will be compared between the two arms. The researchers will also calculate the number of cycles of adaptive therapy participants on arm B completed, and use this information to establish the average. Measurements of quality of life between the participants on both arms will also be compared, as will any reactions from taking the drugs. Lastly, the researchers will measure the time it takes for the lab to provide the ctDNA result after receiving the blood sample. Previous study objectives: Adaptive therapy relies on the competition between drug-sensitive and drug-resistant subclones to control overall tumour growth. It aims to stabilise tumour burden by allowing a significant population of treatment-sensitive cells to survive, which suppresses the proliferation of the less fit, resistant populations. 1. Patients will have circulating tumour DNA (ctDNA) response upon re-introduction of encorafenib plus binimetinib following the first drug holiday. 2. Encorafenib plus binimetinib therapy using adaptive scheduling based on ctDNA level will improve the time to progression, reduce toxicity and enhance quality of life compared to continuous dosing in patients with stage III unresectable or stage IV melanoma. Objectives: To assess whether tumours respond to the re-introduction of encorafenib plus binimetinib following the first period of stopping the drugs. The researchers will do this by measuring the amount of circulating tumour DNA (ctDNA) in the plasma we obtained from the patients' blood samples, which are taken every 2 weeks. Using data from the main objective, they intend to develop a guideline based on the ctDNA levels, to inform doctors when the adaptive treatment should stop and re-start. The researchers compare the ctDNA results from the two arms to identify the average time it takes for participants to respond to the treatment, how long they may remain stable for, or for the disease to worsen. The time it may take for participants' cancer to worsen (known as progression), will be measured at 6, 12 and 15 months from commencing treatment. Also, the median time to the death of participants will be compared between the two arms. The researchers will also calculate the number of cycles of adaptive therapy participants on arm B completed, and use this information to establish the average. Measurements of quality of life between the participants on both arms will also be compared, as will any reactions from taking the drugs. Lastly, the researchers will measure the time it takes for the lab to receive blood and provide the ctDNA result. Background and study aims Encorafenib and binimetinib given in combination is a standard of care treatment in the UK for late-stage cutaneous melanoma, a skin cancer that starts in the cells that produce skin pigmentation. 'Late stage’ means it can't be surgically removed or has spread. The treatment is taken daily. Resistance to the treatment can develop after about 12-15 months. During this period, the treatment will kill the less resistant cells, meaning the tumour has a greater proportion of cells that are resistant to the treatment. This study aims to investigate if the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour as a whole less resistant to the treatment, and increasing the time it takes for the disease to progress. A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every 2 weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume treatment. This treatment is called adaptive therapy. Who can participate? Patients aged 18 years and over with late-stage cutaneous melanoma What does the study involve? Participants are randomly allocated to receive either the standard, daily treatment or adaptive therapy. Patients will receive their allocated treatment until their cancer progresses or there is no longer clinical benefit from taking it, they or their doctor withdraw them from the study, or until the study ends, whichever happens first. As well as the fortnightly visits to the hospital, patients will be required to complete questionnaires to assess their quality of life. These will be completed before their treatment starts, after 4 weeks of treatment, every 12 weeks from when they start treatment and if their cancer progresses or they stop treatment. What are the possible benefits and risks of participating? Participants will delay the commencement of their treatment until all screening and baseline procedures have been completed, which may result in them starting treatment a little later than they would if they were receiving it as routine care. However, if either the patient or treating clinician is of the opinion that this delay would be detrimental to the patient, treatment will commence immediately. Some CT and/or PET-CT scans may be extra to those given as routine care. CT scans use ionising radiation, which may cause cancer many years or decades after exposure. However, the chances of this occurring in the patients recruited to this study are extremely small. Some CT scans require a contrast dye to be used, which may cause bruising or swelling around the injection site. Rarely do some people have an allergic reaction to the dye. Patients with disease in their limbs will undergo PET-CT scans. Patients may get a small bruise or swelling around the area where they inject the radioactive tracer (dye). There is also a risk that the tracer may leak outside of the vein, which may cause swelling and pain in the limb. Rarely, some patients have an allergic reaction to the tracer. Some patients will need to undergo an MRI scan. Being placed into the scanner can make some people feel claustrophobic. Participants will be asked to undergo extra biopsies, but can still participate if they choose not to. The study will be active at hospitals for a period of 3 years. Depending on when a participant commences treatment, they may be involved for between 1 day and 3 years. However, with the exception of the extra visits for blood sampling (explained below), the majority of procedures are as they would receive as part of standard care. Those participants on adaptive therapy will have one 28-day cycle of treatment before it is then withheld, however, the frequency that blood samples are taken to monitor their health and safety will be increased to every 14 days from the standard 28 days. To allow for accurate comparison of results, this increased frequency will also be implemented for participants on the standard treatment too. Although this increase in blood sampling will require more frequent visits to the hospital, it also allows for a 100% increase in the amount of monitoring the participant will receive compared to normal care. All extra visits to the hospital have been mapped to match those for the standard of care as much as possible. Women of childbearing potential will be required to undergo extra pregnancy tests as part of the screening procedure and again at the end of their treatment or when the study ends. This test will be done with a urine sample; however, a blood sample may be required if there is a problem with the urine test. Extra monitoring may also be used if their doctor thinks it is necessary. In addition to those taken as part of routine care, a biopsy (sample) of the tumour will be taken before the patient commences treatment, about 6 weeks later, and again if they relapse. Participants on adaptive therapy will receive stop/start therapy, which may cause them anxiety. They will be reassured that they will be monitored for signs of progression twice as often as they would be normally and, if their ctDNA levels show signs of increasing beyond a pre-determined threshold, they will be advised to immediately recommence the treatment using the 'reserve pack' of tablets they will have been issued. Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? May 2022 to September 2027 Who is funding the study? Jon Moulton Charity Trust (UK) Who is the main contact? DyNAMIc Trial Manager, dynamic_study@liverpool.ac.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-using-blood-test-monitor-guide-treatment-melanoma-dynamic Maximal reduction in percentage mutant copies/ml (ctDNA mutant BRAF copies/ml of plasma) from baseline 2 TAB level upon restart of drugs following first drug off period. Measured longitudinally throughout the study. Current key secondary outcome(s) as of 09/06/2026: 1. ctDNA mutant BRAF copies/ml of plasma. Measured longitudinally throughout the study. 2. Maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria. Measured from Baseline 1 until RECIST progression/clinical deterioration. 3. Percentage of participants who have experienced disease progression or death. Progression Free Survival, defined as time from randomisation to progression (RECIST v1.1 and in Arm B defined as progression whilst on targeted therapy unless stopped due to toxicity/choice). Measured continuously throughout the study. 4. Time to clinical deterioration. Defined as either the point of progression (defined as per RECIST v1.1) or in participants treated beyond progression, at the time of clinically determined deterioration, defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer. Measured continuously throughout the study. 5. Overall survival, defined as time from randomisation until death from any cause. Measured continuously throughout the study. 6. Overall survival, defined as time from randomisation until death from melanoma. Measured continuously throughout the study. 7. Number of adaptive therapy cycles completed. Measured longitudinally throughout the study. 8. Median duration of adaptive therapy cycles. Measured longitudinally throughout the study. 9. Percentage of ctDNA results reported within 5 days from sample receipt into the laboratory. Measured longitudinally throughout the study. 10. EORTC QLQ-C30 and PRO-CTCAE. Measured longitudinally throughout the study. 11. Adverse Events and Serious Adverse Events defined by CTCAE version 5. Measured continuously throughout the study. 12. Number and location of sites of progression. At disease progression on imaging _____ Previous secondary outcome measures as of 01/10/2025: 1. ctDNA mutant BRAF copies/ml of plasma. Measured longitudinally throughout the study. 2. Maximal radiological response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria. Measured from Baseline 1 until RECIST progression/clinical deterioration. 3. Percentage of participants who have experienced disease progression or death. Progression Free Survival, defined as time from randomisation to progression (RECIST v1.1 and in Arm B defined as progression whilst on targeted therapy unless stopped due to toxicity/choice). Measured continuously throughout the study. 4. Time to clinical deterioration. Defined as either the point of progression (defined as per RECIST v1.1) or in participants treated beyond progression, at the time of clinically determined deterioration, defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer. Measured continuously throughout the study. 5. Overall survival, defined as time from randomisation until death from any cause. Measured continuously throughout the study. 6. Overall survival, defined as time from randomisation until death from melanoma. Measured continuously throughout the study. 7. Number of adaptive therapy cycles completed. Measured longitudinally throughout the study. 8. Median duration of adaptive therapy cycles. Measured longitudinally throughout the study. 9. Percentage of ctDNA results reported within 5 days from sample receipt into the laboratory. Measured longitudinally throughout the study. 10. EORTC QLQ-C30 and PRO-CTCAE. Measured longitudinally throughout the study. 11. Adverse Events and Serious Adverse Events defined by CTCAE version 5. Measured continuously throughout the study. 12. Number and location of sites of progression on imaging. At disease progression on imaging _____ Previous secondary outcome measures: 1. Optimised thresholds of percentage reduction in ctDNA mutant BRAF copies/ml as a measure of response to stop drugs and the percentage and/or minimum increase in BRAF mutant copies/ml as a decision to restart drugs, measured longitudinally throughout the study 2. Maximal radiological response (complete response [CR]/partial response [PR]/stable disease [SD]/progressive disease [PD]) to therapy in Arm A vs Arm B measured using RECIST (v1.1) criteria 3. Progression-free survival (PFS) defined as the time from randomisation to radiological progression (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) on Arm A vs Arm B 4. PFS defined as time from randomisation to radiological progression (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) at 6, 12 and 15 months on Arm A vs Arm B 5. Overall survival (OS) defined as the time from randomisation until death in Arm A vs Arm B 6. Number of adaptive therapy cycles completed, recorded longitudinally throughout the study 7. Median duration of adaptive therapy cycles, measured using completed adaptive therapy date longitudinally throughout the study 8. Number and location of sites of disease progression, recorded continuously throughout the study 9. Percentage of ctDNA results provided within 5 working days from sample receipt into CBC, recorded longitudinally throughout the study 10. Maximal reduction in ctDNA mutant BRAF copies/ml for each adaptive cycle, recorded longitudinally throughout the study 11. Rise in ctDNA mutant BRAF copies/ml during drug off period for each patient, recorded longitudinally throughout the study 12. Incidence of CTCAE all grade adverse events in Arm A vs Arm B defined by CTCAE version 5 continuously throughout the study 13. Quality of life measured using EORTC QLQ-C30 and PRO-CTCAE longitudinally throughout the study The study is expected to last for 3 years, analyses of the secondary endpoints will commence once the trial ends. Ethics approval required London - Chelsea Research Ethics Committee

REC London Centre, 2 Redman Place, Stratford

London United Kingdom E20 1JQ 22/LO/0453 10.1186/ISRCTN14643179 1004759 CPMS: 55327, CFTSp175 1004759 55327 CFTSp175 Randomized parallel-arm proof-of-concept study Interventional Randomised controlled trial Treatment 2027-09-30T00:00:00.000Z United Kingdom England Scotland Wales Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge England CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 Guys Hospital

Guys Hospital Great Maze Pond

London England SE1 9RT NV515@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Preston Hospital

Sharoe Green Lane Fulwood

Preston England PR2 9HT Freeman Hospital

Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN Queens Medical Centre

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH 5N896@2.16.840.1.113883.2.1.3.2.4.18.48 John Radcliffe Hospital

Headley Way Headington

Oxford England OX3 9DU RDU5A@2.16.840.1.113883.2.1.3.2.4.18.48 Christie Hospital

Wilmslow Road

Manchester England M20 4BX RM582@2.16.840.1.113883.2.1.3.2.4.18.48 Clatterbridge Cancer Centre

65 Pembroke PLACE

Liverpool England L7 8YA B5N6N@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Marsden Hospital

Royal Marsden Hospital Downs Road

Surrey England SM2 5PT Southampton

Southampton General Hospital Tremona Road

Southampton England SO16 6YD NV163@2.16.840.1.113883.2.1.3.2.4.18.48 Velindre Cancer Centre

Velindre Road

Cardiff Wales CF14 2TL RQFH5@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal Marsden Hospital

Fulham Road

London England SW3 6JJ W5Z3P@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Bournemouth Hospital

Castle Lane East

Bournemouth England BH7 7DW RBD44@2.16.840.1.113883.2.1.3.2.4.18.48 Beatson West of Scotland Cancer Centre

1053 Great Western Road

Glasgow Scotland G12 0YN G517H@2.16.840.1.113883.2.1.3.8.2.16.2 Royal Free Hospital

Pond Street

London England NW3 2QG RAL01@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current key inclusion criteria as of 09/06/2026: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma, including acral 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, or clinically accurately measurable (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function enabling safe administration of the study treatment 10. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month 28 days following last dose of drug (either encorafenib or binimetinib) 12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) Prior to randomisation: 13. BRAF ctDNA level of ≥7 copies/ml of plasma. (If there is a discrepancy between the screening and baseline 1 ctDNA TAB levels this should be discussed via the DyNAMIc trial team at the LCTC.) 14. Left Ventricular Ejection fraction (LVEF) ≥50% of ≥LLN by ECHO _____ Previous key inclusion criteria as of 01/10/2025: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma, including acral 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function as defined below: 9.1. Haemoglobin ≥9 g/dL 9.2. White blood count ≥2 x 10^(9)/L 9.3. ANC ≥1.2 x 10(9)/L 9.4. Platelet count ≥75 x 10^(9)/L 9.5. Albumin ≥2.5 g/dL 9.6. Total bilirubinb ≤1.5 x ULN 9.7. AST or ALT ≤3 x ULN 9.8. Calculated creatinine clearance ≥30 ml/min 10. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month 28 days following last dose of drug (either encorafenib or binimetinib) 12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) At randomisation: 13. BRAF ctDNA level of ≥7 copies/ml of plasma 14. Left Ventricular Ejection fraction (LVEF) ≥50% of ≥LLN by ECHO _____ Previous key inclusion criteria: Patients eligible for the trial must comply with all of the following at randomisation: 1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1) 6. BRAF p.V600E/K/R mutation confirmed (exact point mutation must be known) 7. BRAF ctDNA TAB level of ≥15 copies/ml of plasma 8. ECOG performance status 0/1/2 9. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 10. Adequate organ function as defined below: 10.1. Haemoglobin ≥9 g/dL 10.2. White blood count ≥2 x 10(9)/L 10.3. ANC ≥1.2 x 10(9)/L 10.4. Platelet count ≥75 x 10(9)/L 10.5. Albumin ≥2.5 g/dL 10.6. Total bilirubinb ≤1.5 x ULN 10.7. AST or ALT ≤3 x ULN 10.8. Calculated creatinine clearance ≥30 ml/min 10.9. Left Ventricular Ejection fraction (LVEF) ≥50% or ≥LLN by ECHO 11. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 12. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month following last dose of drug (either encorafenib or binimetinib) 13. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) 14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP participating in the study who are continuously not heterosexually active must still undergo pregnancy testing (as described in inclusion criterion 11) Mixed 18 Years 120 Years All 40 0 Current key exclusion criteria as of 09/06/2026: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (the designation of “active metastasis” should be determined by the local clinical care team in discussion with the DyNAMIc study team at LCTC if needed and informed by recent imaging.) 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study. Discussion via the DyNAMIc trial team at LCTC as to whether they can be included in the study is allowed and the outcome of the discussion will determine entry. 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 11. Prisoners or patients who are involuntarily incarcerated 12. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria as of 15/10/2025: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (patients with prior definitive treatment with immune therapy/radiotherapy (including SRS) or surgery), with no evidence of progression in the last 3 months, can be included 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria as of 01/10/2025: Any patient meeting any of the criteria listed below at baseline will be excluded from study participation: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥6 months ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (patients with prior definitive treatment with immune therapy/radiotherapy (including SRS) or surgery), with no evidence of progression in the last 3 months, can be included 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria: Any patient meeting any of the criteria listed below at baseline will be excluded from study participation: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥6 months following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Metastasis to the brain or leptomeninges 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness 2024-11-29T00:00:00.000Z 2027-03-31T00:00:00.000Z Cutaneous melanoma Cancer Malignant melanoma of skin, unspecified Current interventions as of 01/10/2025: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until progression occurs or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a patient’s bloodstream; treatment on this arm will also cease upon progression or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. When ‘on-treatment’, patients on arm B will receive the SOC dose of both drugs. All participants on arm B will commence with one SOC cycle of both drugs before switching to being ‘off-treatment’. The levels of ctDNA is known as the Tumour Activity Burden (TAB). The ctDNA TAB provides guidance on the resistance levels of the tumour. Pre-defined ctDNA TAB threshold levels are used to indicate when treatment should stop/re-start. These levels will be assessed and reviewed during the trial. All participants, regardless of treatment arm, will provide blood samples for ctDNA TAB analysis every 2 weeks up to progression. Once progression occurs, all participants will be followed up every 3 months until the end of the study, withdrawal or death. Previous interventions: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until relapse occurs. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a patient’s bloodstream; treatment on this arm will also cease upon relapse. When ‘on-treatment’, patients on arm B will receive the SOC dose of both drugs. All participants on arm B will commence with one SOC cycle of both drugs before switching to being ‘off-treatment’. The levels of ctDNA is known as the Tumour Activity Burden (TAB). The ctDNA TAB provides guidance on the resistance levels of the tumour. Pre-defined ctDNA TAB threshold levels are used to indicate when treatment should stop/re-start. These levels will be assessed and reviewed during the trial. All participants, regardless of treatment arm, will provide blood samples for ctDNA TAB analysis every 2 weeks up to progression. Once relapse occurs, all participants will be followed up every 3 months until the end of the study, withdrawal or death. Drug Phase II Encorafenib, binimetinib Data sharing statement to be made available at a later date Protocol

e3f183e4-a274-4ab5-80fb-833fb7584999 df5e103c-3240-4ce0-af72-f940f1be88ad b30d0006-a1a4-4724-853a-0373b3be0528 da4ebc0e-91f8-4129-aa5c-8b5fdf53d436 e4447446-50cb-4d9a-9d5b-44cedd9000af No Protocol file 41841_PROTOCOL_v3.0.pdf 554dafb0-92b3-4ce0-8e97-0f032516655b true application/pdf 3178013 8ab6168325d7c5bfe12452a062639534 Protocol file ISRCTN14643179_Protocol_v4.0_27March2023.pdf 1936664c-5025-445d-822f-54e7fb7a58bc true application/pdf 1918956 dc05e9f6645a3d44b165ff97475adaba Protocol file ISRCTN14643179_Protocol_v5.0_21May2024.pdf 131f8a6c-84ad-41f8-9147-45157d4c17be true application/pdf 3224191 4989a3dcb2b36a8aec14de0343d55da8 Protocol file ISRCTN14643179_Protocol_v6.0_05March2025.pdf 636bc951-4736-4852-bce7-397bfbd1a181 true application/pdf 3223104 27e6dab3d55b57e69ae09bae8240400a Protocol file ISRCTN14643179_Protocol_v7.0_23June2025.pdf fdd89e40-59e4-400d-95fa-ab71ff7da848 true application/pdf 3316457 6730a0120688ba800d59bde40b6d3f26 Protocol file ISRCTN14643179 DyNAMIc_Protocol_V8.0 14Jan2026.pdf 9fe419c0-d703-4211-a814-2b08d9154fc7 true application/pdf 3428955 fd94b17de5266676cfe3456678268262 Paul Lorigan https://orcid.org/0000-0002-8875-2164 Scientific

University of Manchester The Christie NHS Foundation Trust Wilmslow Road

Withington United Kingdom M20 4BX - paul.lorigan@nhs.net Public Paul Lorigan Principal investigator

University of Manchester The Christie NHS Foundation Trust Wilmslow Road

Withington United Kingdom M20 4BX - paul.lorigan@nhs.net Public DyNAMIc Trial Manager Public

Liverpool Clinical Trials Centre Waterhouse Building 1-3 Brownlow Street

Liverpool United Kingdom L69 3GL - dynamic_study@liverpool.ac.uk Public The Christie NHS Foundation Trust Hospital/treatment centre https://ror.org/03v9efr22 Non-commercial Jon Moulton Charity Trust http://dx.doi.org/10.13039/501100023262