16558783 true Effectiveness of ClOmifeNe CitRate for the management of mEn wiTh infErtility (CONCRETE): A randomised double-blind placebo-controlled trial. CONCRETE The primary aim of CONCRETE is to evaluate the efficacy and safety of clomifene as a treatment for men with secondary hypogonadism or idiopathic male infertility compared to placebo. Secondary objective: 1. To determine the efficacy of clomifene in improving semen parameters in this group of men. 2. To determine the efficacy of clomifene in improving the reproductive outcomes in this group of men. 3. To determine the safety of clomifene as a treatment for men with secondary hypogonadism or idiopathic male infertility. 4. To explore the feasibility and acceptability of using clomifene as a primary treatment in this group of men. Background and study aims Male infertility affects many couples trying to conceive. In some men, infertility may be linked to low testosterone levels caused by problems with hormone signals that control the testes (secondary functional hypogonadism), while in others, the cause is unknown (idiopathic male infertility). Clomifene citrate is a medication that is commonly used to treat female infertility and may help improve sperm production in men. However, more research is needed to determine how effective and safe it is for treating male infertility. This study aims to investigate whether clomifene citrate can improve sperm concentration and fertility outcomes in men with secondary functional hypogonadism or idiopathic male infertility compared with a placebo. Who can participate? Men aged 18 to 44 years who have been trying to conceive for at least 12 months and have abnormal semen parameters or secondary functional hypogonadism. What does the study involve? A total of 160 men will take part across several NHS hospitals in the UK. Participants will be randomly allocated to receive either: - One 25 mg clomifene citrate tablet daily - A placebo tablet daily Neither participants nor the study team will know which treatment has been allocated. Participants will take the study medication for 9 months. They will attend follow-up visits at 3, 6, and 9 months, where they will: Provide semen samples for analysis Have blood tests Have health assessments Complete questionnaires about quality of life and sexual health Researchers will also collect information about pregnancies and fertility treatments. A final follow-up assessment will take place 18 months after joining the study. What are the possible benefits and risks of participating? Participants may benefit if clomifene citrate improves sperm production and fertility outcomes. The information collected may help improve future treatment options for men with infertility. Clomifene has a well-established safety profile but may cause mild to moderate side effects. There is also a possibility of interactions with some medications. Participants will be closely monitored throughout the study, including regular blood tests and safety reviews. Where is the study run from? University College London (UCL) Comprehensive Clinical Trials Unit, UK. When is the study starting and how long is it expected to run for? August 2026 to February 2029. Who is funding the study? National Institute for Health and Care Research (NIHR), UK. Who is the main contact? Rumana Jalil, cctu.concrete@ucl.ac.uk Sperm concentration semen analysis (millions per millilitre (millions/mL) the 6-month visit Sperm concentration semen analysis 3-, and 9-month visits Total sperm count as per WHO criteria semen analysis 3-, 6- and 9-month visits Percent of total sperm motility as per WHO criteria semen analysis 3-, 6- and 9-month visits Percent of progressive sperm motility as per WHO criteria semen analysis 3-, 6- and 9-month visits Percent of normal sperm morphology as per WHO criteria semen analysis 3-, 6- and 9-month visits Incidence of spontaneous clinical pregnancy data collection from patient records the 18-month visit Incidence of the need to use any Assisted Reproductive Technology (ART) treatments data collection from patient records the 18-month visit Incidence of pregnancy outcome (spontaneous or with ART) including miscarriage, stillbirth, livebirth and neonatal death data collection from patient records the 18-month visit Time to the first incidence of pregnancy from randomisation data collection from patient records the 18-month visit Incidence of the need to undergo Surgical Sperm Retrieval (SSR) procedure, the type and the outcome of the SSR procedure data collection from patient records the 18-month visit Biochemical outcomes: LH, FSH, Oestradiol, early rise total and free testosterone, oestradiol: testosterone ratio, sex hormone-binding globulin, prolactin, kidney and liver function profile standard medical laboratory methods the 3-, 6- and 9-month visits Clinical outcome: BMI (kg/m2) standard methods the 3-, 6- and 9-month visits Quality of Life outcomes the Male Sexual Health Questionnaire (MSHQ) and the EQ-5D-5L questionnaire the 3-, 6-, 9- and 18-month visits Adverse Events and Reactions (AEs/ARs) at all grades and Serious Adverse Events and Reactions (SAEs/SARs) at all grades data from Case Report Forms (CRFs) any time throughout the duration of the 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/0057 10.1186/ISRCTN16558783 1012496 CPMS: 69132, NIHR: 167189, CTU/2023/46 1012496 69132 167189 CTU/2023/46 Interventional Randomized controlled trial Blinded (masking used) Placebo Single Treatment Safety Not applicable Efficacy Safety Treatment 2029-02-28T00:00:00.000Z United Kingdom England University College London Hospital

250 Euston Road

London England NW1 2PG K2Z3D@2.16.840.1.113883.2.1.3.2.4.18.48 Epsom and St Helier University Hospitals NHS Trust

St Helier Hospital Wrythe Lane

Carshalton England SM5 1AA RVR@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Victoria Infirmary

Queen Victoria Road

Newcastle upon Tyne England NE1 4LP RTFEC@2.16.840.1.113883.2.1.3.2.4.18.48 Southmead Hospital

Southmead Road Westbury-on-trym

Bristol England BS10 5NB NLX59@2.16.840.1.113883.2.1.3.2.4.18.48 St James' University Hospital

Beckett Street

Leeds England LS9 7TF St Marys Hospital

Manchester Royal Infirmary Oxford Road

Manchester England M13 9WL Guy's and St Thomas' NHS Foundation Trust

Guy's Hospital, Great Maze Pond

London England SE1 9RT false 1. Men assigned as biological male at birth 2. Aged ≥18-<45 years inclusive at baseline and randomisation. 3. Diagnosis of primary or secondary infertility at the time of screening, having been trying to conceive for ≥12 months with abnormal semen parameters due to: (i) reduced sperm concentration of ≤16 million spermatozoa per ml on as per the WHO criteria, or (ii) secondary functional hypogonadism (defined as early rise total testosterone ≤12pmol/l) after excluding other causes 4. Capacity to give informed consent Adult 18 Years 45 Years Male 160 0 1. Primary testicular failure (confirmed with an FSH level of ≥15 IU/L) at time of screening 2. History of primary or secondary hypogonadotropic hypogonadism due to other congenital or acquired condition disturbing the hypothalamic-pituitary gonadal axis. 3. History of taking prescribed or non-prescribed hormonal treatment therapy including but not limited to clomifene, gonadotrophins, anabolic steroids and exogenous testosterone. 4. Other causes of male infertility including but not limited to; known obstructive azoospermia, untreated clinical varicocele, history of mumps orchitis, history of chemotherapy/radiotherapy treatment. 5. Abnormal karyotype, evidence of Y chromosome AZF microdeletion, cystic fibrosis gene abnormality, history of cryptorchidism 2026-08-01T00:00:00.000Z 2027-07-31T00:00:00.000Z Male infertility Urological and Genital Diseases Patients will be randomised using the Sealed envelope platform on the computer to receive either 25mg Clomifene Citrate or a matching placebo, to be taken orally once a day for 9 months. • Experimental Arm: 25mg Clomifene Citrate • Control Arm: Placebo Drug Phase II Clomifene citrate Data will be shared based on the following principles: o No data should be released that would compromise an ongoing trial or study. o There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose. o Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data before key trial data are made available to other researchers. o The funder's requirements for data sharing will be adhered to. o The resources required to process requests should not be underestimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. o Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. o Data will be available for sharing after publication of the primary trial results. Researchers wishing to access CONCRETE trial data should contact the Trial Management Group, cctu.concrete@ucl.ac.uk, in the first instance. Available on request 6168ccc5-b858-493d-b7bd-5000123b41b9 13b4685d-380f-4393-ac04-f81662929c52 7daeb074-3030-4a7e-95ad-636d075caa0b 3c0fa431-9be7-4c4f-b2dc-3cd0c21c8523 Yes Rumana Jalil Scientific Public

The Comprehensive Clinical Trials Unit at UCL 90 High Holborn

London United Kingdom WC1V 6LJ +44 20 3108 6584 cctu.concrete@ucl.ac.uk Public Bassel Al Wattar Principal investigator

90 High Holborn

London United Kingdom WC1V 6LJ +44 7510311359 b.wattar@nhs.net Public University College London Comprehensive Clinical Trials Unit Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 17105865 true REFINE-MS: A randomised, rater-blind, phase 3 trial to determine the optimal dose frequency of ocrelizumab for patients with relapsing remitting multiple sclerosis using a novel multi-arm multi-stage frequency-optimisation design REFINE-MS To test whether people with relapsing-remitting MS who have been stable on ocrelizumab for a minimum of 2 years can take it less often and still keep their MS under similar control (measured by looking at whether or not there are any new signs of damage on a brain MRI scan) compared with the standard schedule of every 6 months. Secondary objectives of REFINE-MS are: to determine the effects of taking ocrelizumab less often on how well-controlled the participant’s condition is (including whether or not their disability progresses), participant quality of life, patient reported outcomes and cost-savings to the NHS. Not provided at time of registration. The proportion of participants without new T2 lesions brain MRI scans baseline, 1 year for the Stage 1 (interim) analysis and at 2 years for the Stage 2 (final) analysis Number of new T2 lesions brain MRI 2 years Time-to-relapse the MS relapse notable events reported by site clinician 2 years Annualised relapse rate the MS relapse notable events reported by site clinician 2 years Proportion of participants without disability progression (defined by Expanded Disability Status Scale (EDSS) score increase of ≥1 point or ≥0.5 point if baseline EDSS >5.5) data collected by a blinded rater at site 2 years Rate of adverse events (graded by severity) and infections data reported by site clinician 2 years Rate of whole brain atrophy brain MRI 2 years Proportion of participants with hypogammaglobulinaemia immunoglobulin laboratory test results 2 years Changes in serum neurofilament light concentration laboratory tests results 2 years Changes in cognitive functions assessed by Symbol Digit Modalities Test (SDMT)) data collected by a blinded rater at site 2 years Changes in quality-of-life, patient-reported outcomes, and therapy administration satisfaction EuroQol EQ5D-5L, Multiple Sclerosis Impact Scale (MSIS-29) and the Client Services Receipt Inventory and Work Productivity and Activity Impairment participant-reported outcome measures (PROMs) questionnaires 2 years Ethics approval required East Midlands - Leicester Central Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/EM/0057 10.1186/ISRCTN17105865 1013232 ND004 1013232 ND004 Interventional Randomized controlled trial Blinded (masking used) Active Parallel Treatment Safety Not applicable Efficacy Safety Treatment Other 2030-09-30T00:00:00.000Z United Kingdom England UCLH National Hospital for Neurology and Neurosurgery

Queen Square

London England WC1N 3BG University Hospital Coventry and Warwickshire

Clifford Bridge Road

Coventry England CV2 2DX false 1. Adult participants aged ≥18 yrs 2. Diagnosis of RRMS, according to the 2017 or 2024 revised McDonald criteria 3. Received 4 or more 6-monthly cycles of ocrelizumab (IV or SC) according to NICE TA533 guidelines and the ocrelizumab summary of product characteristics (SPC), prior to randomisation 4. Expanded Disability Status Scale (EDSS) score between 0 and ≤6.5 inclusive at baseline 5. Participants who wish to remain on ocrelizumab 6. Written informed consent provided 7. At randomisation, participants must have a QC-approved Baseline MRI scan (per the MRI Guide), performed up to 6 weeks after the Screening/Baseline/M0 visit Mixed 18 Years 110 Years All 540 0 1. Clinical relapse(s) within 12 months prior to randomisation 2. New MRI lesions prior to randomisation, assessed by the treating site through comparison of the trial baseline scan with the most recent preceding MRI performed at least 3 months earlier while the participant was receiving ocrelizumab 3. Co-treatment with other immunosuppressive medications 4. Any condition or circumstance that prevents the participant from undergoing regular MRI scanning 5. Pregnancy or intention to become pregnant during the study period 2026-05-26T00:00:00.000Z 2028-06-30T00:00:00.000Z Medical condition: Relapsing-remitting multiple sclerosis (RRMS) Medical condition in lay language: A long-term condition affecting the brain and spinal cord, where people experience episodes of new or worsening symptoms (relapses) followed by periods of recovery (remission). Therapeutic areas: Diseases [C] - Nervous System Diseases [C10] Nervous System Diseases Participants will be randomised in the REFINE-MS electronic data capture (eDC) system to receive ocrelizumab (ocrelizumab 600mg intravenous or 920mg subcutaneous). The dose frequency depends on the arm to which the participant is randomised. This trial includes 2 Stages (Stage 1 (divided into 1a and 1b) and Stage 2. In Stage 1a, 6-monthly vs 12-monthly frequencies will be tested, with 100 patients randomised across these two arms. Following this, the study will proceed directly to Stage 1b, in which 3 additional arms will open (9-monthly, 15-monthly and 18-monthly), meaning that participants can be randomised to all five arms. An interim analysis of 12 months of data in 90 of the original 100 participants randomised to 6 vs 12 months will be carried out to determine the design of Stage 2 of the trial. If 12-monthly is not inferior to 6-monthly in terms of proportion of patients with new T2 lesions after one year, patients will continue to be recruited to all five arms; if it is inferior, the trial will convert into a 2-arm non-inferiority trial of 9-monthly vs. 6-monthly frequencies. All participants will be followed up with for at least 2 years. Drug Phase III Ocrevus 300 mg concentrate for solution for infusion [Ocrelizumab] , Ocrevus 920 mg solution for injection [Ocrelizumab] The datasets generated during and/or analysed during the current study will be available upon request (following the publication of the primary outcome) from the REFINE-MS Trial Management Group (contactable via the REFINE-MS trial mailbox mrcctu.refinems@ucl.ac.uk). Data will be shared according to the Clinical Trials Unit’s controlled access approach, based on the following principles: • No data should be released that would compromise an ongoing trial or study. • There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose. • Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers. • The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. • Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries. • Only tabulated, pseudonymised data will be shared. • Data Transfer Agreements and relevant approvals will be sought. • Participant consent will be sought for use of data for future research via the main trial consent form when participants join the study. Data will be available for sharing following publication of the primary outcome. Researchers wishing to access REFINE- MS data should contact the Trial Management Group in the first instance. Any remaining samples collected as part of the mechanistic immunology substudy will be destroyed at the end of the trial and therefore will not be available for future research. Available on request 2bf3d7dd-0e96-498d-80ea-08c8c95fad7a 6683d322-7759-431e-9f66-db840bd3b3c1 17d9404c-fc36-442c-9c34-a00c42f58261 c0ebeb7f-cb35-470f-a23f-181885b42a1d Yes - REFINE-MS Team Public

MRC CTU at UCL, ICTM 2nd Floor, 90 High Holborn

London United Kingdom WC1V 6LJ - mrcctu.refinems@ucl.ac.uk Public Olga Ciccarelli Scientific Principal investigator

10-12 Russell Square

London United Kingdom WC1B 5EH +44 (0)7950949908 o.ciccarelli@ucl.ac.uk Public University College London https://ror.org/02jx3x895 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 17108793 true Alzheimer’s Disease - Systematic Multi-Arm Adaptive Randomised Trial (AD-SMART) AD-SMART The main objective is to demonstrate therapeutic benefit, on clinically oriented outcome measures, of selected compounds when compared with standard-of-care plus placebo. For the first 2 treatment arms, selected compounds will be repurposed medications tested over several years using the multi-arm multi-stage (MAMS) trial design, so that new research treatments can be added when appropriate. Novel drug treatments, including compounds developed and proposed by industry, will be considered for future arms. The primary objective for the analyses of activity at the end of interim analysis stages 1 and 2 and the final analysis of efficacy at the end of stage 3 will be to detect a difference in the rate of change in score over 18 months on at least one of the co-primary outcomes: the rate of change in Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the rate of change in score on the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). To assess the effects of candidate drugs over 18 months on: • Neuropsychiatric symptoms (NPI) • Quality of life • Caregiver burden • Thinking ability and cognitive impairment • Establish the safety profile of the IMPs in Alzheimer’s Disease. Background and study aims Research into Alzheimer’s disease is making progress, but big challenges remain. The proposed project, AD-SMART, is a quicker, more efficient way of identifying effective treatments for Alzheimer’s. The trial will be for a period of about four years. It will test whether either of two existing medicines (atomoxetine and immediate-release (IR) metformin) can relieve and improve symptoms in patients with Alzheimer’s. Currently, they are used for other illnesses and are known to be safe and effective for those diseases. It will also assess each treatment’s side effects (if any), whether they improve quality of life, and offer the health service sufficient value for money. Who can participate? Patients with symptoms of Alzheimer’s disease. What does the study involve? The trial will compare current standard care and each of two treatments with that care. There will also be a dummy treatment, known as a placebo. The drugs were chosen by an international panel review process, together with patient and public input. A drug treatment will be considered successful in AD-SMART if, over 18 months, it is both safe and shows a meaningful difference to patients’ quality of life in one or more of the following measures: • cognitive symptoms (e.g. memory, problem solving). • ability to perform daily activities (e.g. showering, cooking). These will be tested in person at the start of the trial, and at intervals of six, twelve and eighteen months. The research team will collect blood samples at the same time as these clinical tests to learn how changes in levels of certain blood markers are linked to the progression and severity of Alzheimer’s. They will also conduct MRI scans at the start and end of the trial to look for changes in brain structure. This information will allow us to improve our understanding of how the treatments work to reduce symptoms and affect the progression of the disease. Following the screening and baseline appointments and once randomisation in the trial database is complete, participants will be contacted for follow-up visits with an additional weekly telephone call during the 4-week titration phase. Trial treatment should ideally be started within 2 weeks of randomisation. The screening, randomisation, week 26, week 52 and week 78 visits must be conducted in person at the AD-SMART trial site. All other study visits can be conducted remotely (via video or telephone). If bloods are required for a remote labelled visit, these can be collected via primary care or other phlebotomy clinics and results provided to the site team. Participants will only move up in titration if the dose is tolerated, there are no adverse events, or the clinician deems it appropriate to move up in titration if there is an adverse event reported, and only after the telephone assessment. Prior to entering the study, the participant will be asked to have a blood test and an ECG for safety tests. Additional research blood samples for translational work will also be requested at baseline, week 26, week 52 and week 78 (final visit). At the same time, the participant and their study partner will be asked to complete several assessments and questionnaires each visit to assess how they are living with AD, e.g. the EQ-5D-5L, ZBI, A-IADL-Q-SV (at baseline, week 26, week 52 and week 78). What are the possible benefits and risks of participating? It is hoped that participants will be helped by having any of the medications in this study, but this cannot be guaranteed. That is the reason the study is being conducted. It is possible that the results may not help the participants, but the information obtained from this study will help us to improve treatment for future patients with AD. The tests completed as part of the trial may find other health care concerns or illnesses that may be affecting the trial participants. If they do, the study team will follow their usual process to address these. This may include informing their GP so that they can follow up with them. If benefit is shown, an application will be submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) with supporting documentation showing its effect. The MHRA will review this and ensure it meets the strict standards for quality, safety and effectiveness before licensing it for use within mild to moderate Alzheimer’s Disease. This information will then be passed on to the National Institute for Health and Care Excellence (NICE), which will assess the cost-effectiveness for the NHS to fund the medication. If approved, the medication will then be available on the NHS as treatment for mild to moderate Alzheimer’s Disease. Licensing may also be applied for in other countries around the world. Questionnaires: Some of the questions asked may be upsetting, or the participant and their study partner may feel uncomfortable answering them. Blood samples: Taking blood from a participant's arm may cause faintness and/or swelling, pain, redness, bruising, bleeding at the collection site, or infection (infection rarely happens) at the site where the needle is inserted. Electrocardiogram (ECG): Skin irritation is rare but could occur during an ECG from the electrode patches or gel that is used. Whilst MRI scans are part of standard care for AD, some people find it uncomfortable to have the scans due to the need to lie still or claustrophobia. Some people are unable to have an MRI due to other clinical reasons. If this is the case, the participant will not have to have an MRI test to take part in the study. The AD-SMART trial treatments, atomoxetine and IR metformin, are repurposed drugs and therefore have a well-known safety profile. The participant might experience different or extra side effects from the treatments that they take in this study. If a participant is experiencing adverse events, it is clinical discretion whether they should be assessed in person. There is a potential risk that an analysis at stage 1 and 2 may result in a treatment arm being discontinued before it has a chance to have any cognitive effect. Against this has to be balanced the risk of continuing randomisation to a clinically ineffective treatment longer than necessary. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? January 2026 to March 2031 Who is funding the study? 1. UK Dementia Research Institute (UK) 2. The National Institute for Health and Care Research (UK) Who is the main contact? mrcctu.adsmart@ucl.ac.uk Severity of cognitive symptoms of dementia the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) baseline, month 6, month12 and month18 (end of study) Functional impairment for instrumental activities of daily living the Amsterdam IADL Questionnaire (A-IADL-Q short version) baseline, months 6, 12 and 18 (end of study) Neuropsychiatric and behavioural symptoms the Neuropsychiatric Inventory (NPI), a structured, informant-based interview baseline, months 6, 12 and 18 (end of study) Participant health-related quality of life the EQ-5D-5L baseline, months 3, 6, 12, 15 and 18 (end of study) Caregiver burden the Zarit Burden Interview (ZBI) baseline, months 6, 12 and 18 (end of study) Safety Profile of IMPs, including all adverse events, serious adverse events, adverse reactions, and suspected unexpected serious adverse reactions, the systematic collection, assessment, and analysis of safety data throughout the study, from the first dose until the end of follow-up one time point Use of health and social care resources a structured Resource Use Questionnaire baseline covering preceding 6 months, and months 6, 12 and 18 Ethics approval required Fulham Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/LO/0919 10.1186/ISRCTN17108793 1012878 CPMS: 70766, ND003 1012878 70766 ND003 Interventional Randomized controlled trial Blinded (masking used) Placebo Parallel Treatment Not applicable Efficacy Safety 2031-03-31T00:00:00.000Z United Kingdom England Scotland Windsor Research Unit

Cambridgeshire & Peterborough NHS Foundation Trust Fulbourn Hospital

Cambridge England CB21 5EF Two Bridges Research & Development Clinic

Surrey and Borders Partnership NHS Foundation Trust Guildford Street

Chertsey England KT16 9AU The Anne Rowling Regenerative Neurology Clinic

Chancellor’s Building, University of Edinburgh 49 Little France Crescent

Edinburgh Scotland EH16 4SB Memory Assessment & Research Centre (MARC)

Tom Rudd Unit Moorgreen Hospital Botley Road, West End

Southampton England SO30 3JB false Patient Core Inclusion Criteria: 1. Adults aged ≥55 years on the day of screening, no upper age limit 2. Either: 2.1. Confirmed clinical diagnosis of Alzheimer’s Disease (AD) 2.2. Confirmed clinical diagnosis of Mixed Dementia consisting of Alzheimer's Disease and Vascular Dementia 3. Mini Mental State Examination score of ≥17 4. Confirmatory blood biomarker testing (pTau-217) (positive or intermediate via validated assays) ≤ 365 days prior to screening or between screening and randomisation or a positive amyloid PET scan (if available) or a positive amyloid CSF test (if available) 5. Randomisation should ideally take place within 4 weeks of the screening visit but no later than 8 weeks after the screening visit 6. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation 7. Willing and able to have MRI scans in accordance with the assessment schedule unless participant is clinically contraindicated due to: 7.1. Pacemakers or defibrillators (unless MRI-conditional models) 7.2. Aneurysm clips, stents or metal implants (unless MRI safe) 7.3. Cochlear implants (unless MRI-conditional models) 7.4. Metal fragments in the body 7.5. Severe claustrophobia 8. Negative pregnancy test ≤4 weeks prior to randomisation for women of child-bearing potential 9. Normal liver function at screening consisting of all the following: 9.1. Total serum bilirubin <1.5 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of total serum bilirubin is 51.3 μmol/l or 3mg/dl) 9.2. Alanine aminotransferase (ALT) <3 x ULN; 9.3. Alkaline phosphatase <3 x ULN 10. Documented participant and study partner informed consent 11. If a participant is being re-randomised into the trial, additional timing of entry requirements must also be met: 11.1. For participants being re-randomised after completing 18 months’ follow-up and the arm was not closed due to lack of activity, a 12-week washout period from last dose of IMP must be completed before their screening visit. If the efficacy analysis indicates that the IMP was ineffective then this washout period can be reduced to 6 weeks. 11.2. For participants being re-randomised following treatment arm termination due to lack of activity, a 6-week washout period from their last dose of IMP must be completed prior to screening assessment. See Section 5.4 of the main Protocol for further details on the re-randomisation process. Study Partner inclusion criteria: 1. Participant that meets the AD-SMART eligibility criteria has consented to participation in the trial 2. Has at least twice-weekly contact with participant 3. Be 18 years or older at the time of providing consent 4. Willing to complete study partner questionnaires as outlined in visit schedule 5. Willing to attend remote and in-person study visits with participant 6. Documented informed consent Mixed 55 Years 120 Years All 1200 0 Patient exclusion criteria: 1. Fazekas Score =3 reported from an MRI taken at any time prior to randomisation, if an MRI is not clinically contraindicated (reasons specified in Inclusion Criteria 7) 2. MRI does not need to be repeated if Fazekas score = 0, 1 or 2 reported from an MRI performed ≤365 days to screening visit (if Fazekas score has not been reported, refer to Section 7.4) 3. MRI should be conducted if participant is not clinically contraindicated to MRIs and previous MRI where Fazekas score = 0, 1 or 2 was >365 days or previous MRI scan is not available for Fazekas score reporting or participant has never had an MRI (refer to Section 7.4) 4. Clinical diagnosis of Dementia with Lewy bodies 5. Clinical diagnosis of Parkinson’s disease 6. Clinical diagnosis of Frontotemporal Dementia 7. Cardiac failure (American Heart Association Stage C or D) 8. Significant respiratory comorbidity (hospitalisation within the previous ≤6 months due to respiratory comorbidity) 9. Renal failure (CKD IV or eGFR ≤45 mL/min/1.73m²) at any time point prior to randomisation 10. Malignancy (except if in complete remission) e.g. solid organ or haematological or melanoma 11. Individuals without an identified study partner (refer to Section 4 for further details on study partners) 12. Individuals who have an Alzheimer’s Disease or Central Nervous System medication (e.g. antidepressant) change or dose change ≤28 days prior to screening 13. Use of an Investigational Medicinal Product (IMP) or Investigational Medical Device (IMD) ≤26 weeks prior to randomisation (except for AD-SMART participants that are being re-randomised. See Section 5.4 for further information). 14. Receiving antibody-based amyloid clearing treatment for Alzheimer's Disease within 6 months prior to randomisation 15. Unable or unwilling to comply with study procedures 16. Unable to swallow whole capsules 17. Individuals who are living in the same household as an AD-SMART participant who is actively taking trial medication 18. Female participants that are pregnant or breastfeeding 19. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (see Appendix 1) whilst on trial treatment and up to 12 weeks after the last dose of study drug 20. Male participants with a partner of child-bearing potential unwilling or unable to use an acceptable method of contraception whilst on trial treatment and up to 12 weeks after the last dose of the study drug. 21. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment 22. Current or previous exposure to any of the currently recruiting AD-SMART IMPs ≤26 weeks before randomisation. 23. History of alcohol and/or drug abuse and/or dependence within the 5 years prior to screening visit. 24. Any concurrent medical condition, abnormal laboratory tests or uncontrolled, clinically significant systemic disease that, in the opinion of the Investigator, could cause study participation to be detrimental to the participant. 25. Participants who are not eligible for any of the trial IMPs, according to the eligibility criteria listed in the individual drug appendices. Please note that participants can enter the trial if they are eligible for at least one of the trial treatment arms, but do not need to be eligible for all. Information on repeating screening tests due to abnormal results and re-completing the screening visit can be found in Section 3.5.5 of the main Protocol. If a treatment arm is stopped early following interim analysis, or a new treatment arm is introduced to the trial, the overall and treatment-specific inclusion/exclusion criteria will be reassessed and updated as needed. Arm-specific eligibility criteria: Atomoxetine-specific exclusion eligibility criteria: In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 1 Atomoxetine’ for the arm-specific exclusion eligibility criteria for the Atomoxetine arm which must also be met. Metformin-specific exclusion eligibility criteria: In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 2 Metformin’ for the arm-specific exclusion eligibility criteria for the metformin arm which must also be met. 2026-05-01T00:00:00.000Z 2029-09-30T00:00:00.000Z Medical condition: Symptomatic Alzheimer’s Disease (Mild Cognitive Impairment, Mild Dementia, Moderate Dementia) Medical condition in lay language: Alzheimer’s disease (AD) Therapeutic areas: Diseases [C] - Nervous System Diseases [C10] Nervous System Diseases The AD-SMART trial will test whether either Atomoxetine or Immediate Release (IR) Metformin can relieve and improve symptoms in patients with Alzheimer’s. Currently, they are used for other illnesses and are known to be safe and effective for those diseases. We will also assess each treatment’s side effects (if any), whether they improve quality of life, and offer the health service sufficient value for money. The trial will compare current standard care and each of two treatments with that care. There will also be a dummy treatment, known as a placebo. Randomisation will be performed centrally at MRC CTU. Each participant will be randomised using their unique participant identification number that was allocated sequentially at screening. Eligibility and consent will be verified before each participant is randomised. If participants are ineligible for a specific research arm, they can be assessed for eligibility and randomised to other open arms. Trial treatment should be started within 2 weeks of randomisation and will continue over the course of 18-month follow up. Follow up will continue until the study ends, regardless of whether participants discontinue treatment (either temporarily or permanently). An electronic prescription will be produced and approved by a delegated staff member at the participant’s site. The electronic prescription will be provided to the central pharmacy, which will dispense and courier the IMP to the participant’s home address. There will be a 4-week titration phase, and participants will be dispensed 1 bottle containing 100 pills. Participants will only move up in titration if the dose is tolerated, there are no adverse events, or the clinician deems it appropriate to move up in titration if there is an adverse event reported. Following completion of the titration phase and confirmation of tolerability, participants will receive 200 capsules per bottle, 2 bottles received every 3 months, if the participant is on dose 3 or dose 4. They will only receive 1 bottle if they are on dose 1 or dose 2. Arm A participants will receive placebo capsules with microcrystalline cellulose or pregelatinized starch, Arm B participants will receive Atomoxetine 25mg capsules, over-encapsulated in DBCaps capsules with pregelatinized starch as a backfill. Arm C participants will receive over-encapsulated immediate-release metformin: 500mg in week 1, 1000mg in week 2, 1500mg in week 3 and 2000mg from week 4 to week 78, in the form of 500mg capsules in addition to their usual SoC. A drug treatment will be considered successful in AD-SMART if, over 18 months, it is both safe and shows a meaningful difference to patients’ quality of life in one or more of the following measures: (i) cognitive symptoms (e.g., memory, problem solving). (ii) neuropsychiatric symptoms (e.g., mood, anxiety, apathy). (iii) ability to perform daily activities (e.g., showering, cooking). These will be tested in person at the start of the trial, and at intervals of 6, 12 and 18 months. Our research teams will collect blood samples at the same time as these clinical tests to learn how changes in levels of certain blood markers are linked to the progression and severity of Alzheimer’s. We will also conduct MRI scans at the start and end of the trial to look for changes in brain structure. This information will allow us to improve our understanding of how the treatments work to reduce symptoms and affect progression of the disease. Drug Phase III Metformin [Metformin Hydrochloride] , Atomoxetine 25 mg hard capsules [Atomoxetine Hydrochloride] , Metformin [Metformin Hydrochloride] Research teams may approach the MRC CTU (mrcctu.adsmart@ucl.ac.uk) with a formal data-sharing request detailing the specific requirement, proposed research, qualification of researchers and publication plan if they are interested in using AD-SMART data. The request will be reviewed by the trial committees. Data and/or samples will be available for sharing following the end of a trial arm and the unblinding of participants. Researchers wishing to access the AD-SMART Trial data should contact the Trial Management Group in the first instance. Following trial completion, requests for data and/ or sample sharing will be reviewed by an AD-SMART access committee, which will include the trial’s Chief Investigators. Data and/ or samples will be shared during the trial according to the CTU’s controlled access approach, based on the following principles: 1. No data and/or samples should be released that would compromise an ongoing trial or study. 2. There must be a strong scientific or other legitimate rationale for the data and /or samples to be used for the requested purpose. 3. Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data and /or samples before key trial data are made available to other researchers. 4. The resources required to process requests should not be underestimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. 5. Data and/ or sample exchange complies with Information Governance and Data Security Policies in all of the relevant countries. 6. Data and/ or sample exchange is only provided following the execution of a valid material transfer agreement (MTA). Anonymised study data will be made available on appropriate data-sharing platforms. Available on request cd468436-4512-4c34-a8c6-ac12c31c5ec0 7635ea53-5530-4860-b020-cd0a0045e4c6 f592f00d-150c-4cb4-b876-b149adaa0361 7c6f2b7a-7a04-4ff0-9f87-e4c58ada84fe Yes Shabinah Ali Scientific Public

2nd Floor, 90 High Holborn

London United Kingdom WC1V 6LJ +44 (0)207 670 4700 mrcctu.adsmart@ucl.ac.uk Public Paresh Malhotra Principal investigator

Imperial College London, Charing Cross Campus (3N), Fulham Palace Rd

London United Kingdom W6 8RF +44 (0)207 594 1081 p.malhotra@imperial.ac.uk Public University College London https://ror.org/02jx3x895 Non-commercial UK Dementia Research Institute http://dx.doi.org/10.13039/501100017510 17592593 true EAT-UP - Extended Antibiotic Treatment in chronic UTI Patients; a Phase II safety and efficacy trial EAT-UP The primary objective is to assess the safety, feasibility and efficacy of using an extended treatment (high) dose of one of the following antibiotics: cefalexin, trimethoprim or nitrofurantoin, in combination with the urinary antiseptic methenamine hippurate compared to standard prophylactic (low) dose treatment with cefalexin, trimethoprim, nitrofurantoin, amoxicillin, or methenamine hippurate alone in the treatment of chronic urinary tract infection (UTI) in women. Efficacy will be determined using the primary outcome: the reduction of urinary white blood cell (WBC) counts, an indicator of infection, at the 12-week timepoint. Safety will be measured by how many side effects, also called adverse events, are reported by the participants. Feasibility will be determined by comparing compliance rates (how well participants follow the treatment plan) between treatment arms. Secondary objectives of the trial are assessing the following between the treatment arms: 1. How many times people needed rescue treatment (medications given when a participant experiences a flare in their UTI symptoms) throughout the trial 2. Changes in bacteria within the gut over the course of treatment by using perineal swab samples to check for antibiotic-resistant bacteria, particularly E. coli 3. Changes in bacteria within the urinary tract over the course of treatment by using urine samples to identify which bacteria are present, how many are found, and how sensitive or resistant they are to different antibiotics 4. Side effects reported 5. Health-related quality of life and disease symptoms as reported by the participant 6. Treatment satisfaction as reported by the participants 7. Impression of improvement in symptoms as reported by the participant 8. How well participants took the medication as prescribed Background and study aims Chronic urinary tract infection (UTI) is a condition where patients experience persistent urinary tract infections with daily symptoms. It is a recently recognised type of UTI. Currently, treatment for chronic UTI follows NICE guidelines for recurrent UTIs (characterised by frequent infections with symptom-free periods in between). This includes short courses of treatment-dose antibiotics, extended courses of low-dose prophylactic antibiotics or methenamine hippurate monotherapy. These treatments are often ineffective for chronic cases. The purpose of this trial is to assess whether extended courses of treatment (higher) dose antibiotics, combined with the urinary antiseptic methenamine hippurate, is more effective at treating chronic UTI than standard treatment of either low-dose prophylactic antibiotics or methenamine hippurate monotherapy over 12 weeks. It will also assess whether this approach is safe and feasible. The trial will also use fresh urine microscopy to detect white blood cells as an indicator of infection, as standard tests used in the NHS, such as urine cultures and dipstick analysis, often fail to identify chronic infections. Who can participate? Patients aged 18 years and over who have experienced chronic UTI symptoms for at least 3 months What does the study involve? Participants will be randomly assigned into one of two groups: Group 1 will receive a treatment dose antibiotic in combination with the urinary antiseptic, methenamine hippurate (1 g twice daily). The treating clinician will select one of the following antibiotics based on the individual needs of the participant, such as their medical history, concomitant medications and any known allergies: 1. Cefalexin (500 mg four times daily), or 2. Nitrofurantoin (100 mg twice daily), or 3. Trimethoprim (200 mg twice daily) Group 2 will receive a low-dose prophylactic antibiotic or the urinary antiseptic, methenamine hippurate. The treating clinician will select one of the following treatments based on the individual needs of the participant, such as their medical history, concomitant medications and any known allergies: 1. Amoxicillin (250 mg once daily), or 2. Cefalexin (125 mg once daily), or 3. Nitrofurantoin (50 mg once daily), or 4. Trimethoprim (100 mg once daily), or 5. Methenamine hippurate (1 g twice daily) Participants will be taking trial medication for 12 weeks and will be required to attend clinic for assessments every 4 weeks. Participant will complete questionnaires and provide blood, urine, and perineal (the area between the vagina and anus) swabs samples. What are the possible benefits and risks of participating? The goal of the trial is to find a more effective way to manage chronic UTI, reducing symptoms and improving quality of life for patients with this condition. If successful, this study may support changes to treatment guidelines and lead to better outcomes for those living with chronic UTI. Although all antibiotics used in the trial (amoxicillin, cefalexin, nitrofurantoin, and trimethoprim), and methenamine hippurate, are widely used and generally well tolerated, there remains a potential risk of side effects for participants. Common side effects associated with the trial antibiotics include diarrhoea, nausea, indigestion, vomiting, skin rashes, urticaria (a skin reaction causing raised, red, and itchy welts or patches on the skin), headache, and fungal infections. In addition, Trimethoprim commonly causes hyperkalaemia (high potassium levels in the bloods), while nitrofurantoin has been very rarely linked to acute pulmonary damage. The frequency of anaphylactic reactions varies and is not always well documented; however, available data suggests they are very rare with amoxicillin and trimethoprim, and unknown for nitrofurantoin and cefalexin. Methenamine Hippurate may cause nausea, vomiting, and bladder irritation; haematuria (blood in the urine) is a rare side effect. Participants will be informed of all potential adverse events during the informed consent process and they will be advised to monitor and report any side effects to their research team. All participants will be provided with a patient safety card which contains the contact details of the research team in and out of office hours and they will be advised to carry with them at all times. In addition to minimise the risks associated with laboratory abnormalities; blood tests will be conducted every 4 weeks to detect any abnormal results. The trial protocol includes specific guidance on managing abnormal blood findings and outlines how and when IMP adjustments should be made. Some of the IMPs carry potential risks during pregnancy, as outlined in the Summary of Product Characteristics for each drug. Trimethoprim is contraindicated during pregnancy, particularly in the first 12 weeks, due to its impact on folic acid levels. Nitrofurantoin is contraindicated during labour and delivery because of the risk of haemolysis in the infant’s immature red blood cells. Additionally, all IMPs are excreted in breast milk. Based on this information, the trial excludes participants who are pregnant (or planning pregnancy during trial participation) or breastfeeding. Additionally, individuals of childbearing potential who are unwilling or unable to use an acceptable method of contraception for the duration of the trial and for one week after the final dose will also be excluded. All participants of childbearing potential will be required to complete a urine pregnancy testing at the screening visit and at all other scheduled trial visits. The collection of blood samples can be uncomfortable but rarely results in any serious problems. Reported side effects include feeling light-headed or faint, bruising and/or discomfort around the needle site. Every effort will be made to minimise this. Blood samples will be taken at every visit. Where is the study run from? University College London Comprehensive Clinical Trials Unit (UK) When is the study starting and how long is it expected to run for? February 2025 to April 2028 Who is funding the study? Medical Research Council (UK) Who is the main contact? The EAT-UP Trial Team, cctu.eat-up@ucl.ac.uk Urinary white blood cell (WBC) count measured using fresh urine microscopy at baseline, week 4, week 8 and week 12, used as the principal biomarker to indicate urinary tract inflammation. 1. The impact of lower urinary tract symptoms (LUTS) on a participant’s quality of life is measured using Lower Urinary Tract Symptoms quality of life (ICIQ-LUTSqol) scores at baseline, Week 4, Week 8 and Week 12 2. Participant’s experience of urinary tract symptoms is measured using Whittington 39-point Lower Urinary Tract Symptoms (W-39 LUTS) scores at baseline, Week 4, Week 8 and Week 12 3. Participant’s generic quality of life is measured using EuroQol EQ-5D 5-Level Health Related Quality of Life Questionnaire (EQ-5D-5L) scores at baseline and Week 12 4. Participant’s perception of change in their condition following treatment is measured using Patient Global Impression of Improvement (PGI-I) scores at Week 4, Week 8 and Week 12 5. Participant’s satisfaction with treatment will be measured using Lübeck Medication Satisfaction (LMS) Questionnaire scores at Week 12 only 6. Frequency of rescue therapy use for participants requiring further treatment escalation for an acute flare of symptoms will be collected at Week 4, Week 8 and Week 12 7. Treatment adherence is measured by The Medication Adherence Report Scale (MARS-5) scores at Week 4, Week 8 and Week 12 8. Safety and tolerability as indicated by changes in vital signs, weight, clinical laboratory measures and adverse events will be measured at Baseline, Week 4, Week 8 and Week 12 9. Participant’s urine will be tested to evaluate the changes in the type of bacteria found in the urine, the amount of bacteria and how the bacteria is responding to antibiotics (urine culture species, cfu/ml count, sensitivities and resistance profiles) at baseline and Week 12 10. Changes in perineal swab analyses will be used to measure any changes in how bacteria in the gut responds to antibiotics (including the E. coli identified, sensitivities and resistance profiles) at baseline and Week 12 Ethics approval required Wales Research Ethics Committee 3

Health and Care Research Wales, Floor 4, Crown Building

Cardiff United Kingdom CF10 3NQ 25/WA/0300 10.1186/ISRCTN17592593 1011957 NCT07202949 CTU/2019-342 NCT07202949 1011957 CTU/2019-342 Open randomized controlled parallel-group trial Interventional Randomised controlled trial Efficacy Safety 2028-04-30T00:00:00.000Z United Kingdom England The Whittington Hospital

Highgate Hill

London England N19 5NF RJ135@2.16.840.1.113883.2.1.3.2.4.18.48 Freeman Hospital

Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTF90@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospital

235 Euston Road

London England NW1 2BU St Mary's Hospital

Manchester University NHS Foundation Trust Grafton Street

Manchester England M13 9WU Patient Current key inclusion criteria as of 05/02/2026: 1. A diagnosis of chronic UTI, without structural or functional urinary tract abnormality*, defined as daily persistent symptoms affecting storage (urinary frequency, urgency or urge incontinence) and urinary tract pain symptoms (including bladder pain, urethral pain, or dysuria), for at least 3 months prior to the screening visit, with previously associated transient symptomatic improvement to antibiotic treatment for UTI, which in the opinion of the delegated clinician is secondary to chronic urinary tract infection. 2. A fresh urine microscopy examination showing ≥20 white blood cells/µl of urine at the screening visit. 3. Female** patients. 4. Aged ≥18 years. 5. Screening blood result of eGFR ≥45ml/min/1.73m2. 6. Able and willing to attend trial visits and comply with all study procedures for the duration of the trial. 7. Able and willing to provide informed consent prior to any study related assessments and/or procedures. * A structural or functional abnormality may include kidney reflux, current or long-term catheter use, renal transplant, diversion surgery, renal stones, grade 2 or above utero-vaginal prolapse or incomplete bladder emptying. ** For the purposes of this trial, a female will be defined as an individual assigned female at birth who has a female urinary tract. _____ Previous key inclusion criteria: 1. A diagnosis of chronic UTI, without structural or functional urinary tract abnormality*, as defined as daily persistent symptoms affecting storage (urinary frequency, urgency or urge incontinence) and urinary tract pain symptoms (including bladder pain, urethral pain, or dysuria), for at least 3 months, with previously associated transient symptomatic improvement to antibiotic treatment for UTI, which in the opinion of the delegated clinician is secondary to chronic urinary tract infection 2. A fresh urine microscopy examination showing ≥20 white blood cells/µl of urine at the screening visit 3. Female** patients 4. Aged ≥18 years 5. Screening blood result of eGFR ≥45ml/min/1.72 m2 6. Able and willing to attend trial visits and comply with all study procedures for the duration of the trial 7. Able and willing to provide informed consent prior to any study related assessments and/or procedures * A structural or functional abnormality may include kidney reflux, current or long-term catheter use, renal transplant, diversion surgery, renal stones, grade 2 or above utero-vaginal prolapse or incomplete bladder emptying. ** For the purposes of this trial, a female will be defined as an individual assigned female at birth who has a female urinary tract. Mixed 18 Years 100 Years Female 192 0 Current key exclusion criteria as of 05/02/2026: 1. Inability to take at least one of the following antibiotics: Cefalexin, Nitrofurantoin, or Trimethoprim, at prophylactic and treatment dose according to NICE guidelines, and/or the Summary of Product Characteristics (such as hepatic or renal dysfunction), or any other medical contraindications. 2. Inability to take methenamine hippurate due to medical contraindications. 3. Current use of immune-modulating drugs for the treatment of chronic illnesses such as rheumatoid arthritis, chronic lung disease, any other autoimmune conditions or cancer. 4. Current use of Sodium-Glucose Transport Protein 2 (SGLT2) inhibitors*. 5. A current diagnosis of bladder cancer. 6. A diagnosis of an active sexually transmitted infection or a recent diagnosis of a sexually transmitted infection within the last 3 months of the screening visit. 7. Previous use of an antibiotic at treatment dose as per NICE guidelines for more than 14 consecutive days for treatment of UTI in the last 3 months prior to the screening visit. 8. Pregnancy (or planned pregnancy during trial participation) and/or breastfeeding. 9. Women of childbearing potential that are unable/unwilling to use an acceptable method of contraception (as described in section 3.4.1) to avoid pregnancy for the duration of the trial and for 1 week after the last dose of trial medication. 10. Current participation in another clinical trial of a device, interventional medicinal product, advanced therapy, or surgical procedure; or previous participation within 6 months of the screening visit. 11. Any medical condition or previous treatment which in the investigator’s opinion compromises the potential participant’s ability to participate. *Patient’s must not have taken a Sodium-Glucose Transport Protein 2 (SGLT2) inhibitor within 24 hours before the screening visits to be eligible for the trial. _____ Previous key exclusion criteria: 1. Inability to take at least one of the following antibiotics: cefalexin, nitrofurantoin, or trimethoprim, at prophylactic and treatment dose according to NICE guidelines, and/or the Summary of Product Characteristics (such as hepatic or renal dysfunction), or any other medical contraindications (such as allergies, intolerances or concomitant medications). 2. Inability to take methenamine hippurate due to medical contraindications. 3. Current use of immune-modulating drugs for the treatment of chronic illnesses such as rheumatoid arthritis, chronic lung disease, any other autoimmune conditions or cancer. 4. Current use of Sodium-Glucose Transport Protein 2 (SGLT2) inhibitors*. 5. A current diagnosis of bladder cancer. 6. A diagnosis of an active sexually transmitted infection or recently diagnosed with a sexually transmitted infection within the last 3 months. 7. Previous use of an antibiotic at treatment dose as per NICE guidelines for more than 14 consecutive days for treatment of UTI in the last 3 months. 8. Pregnancy (or planned pregnancy during trial participation) and/or breastfeeding. 9. Women of childbearing potential that are unable/unwilling to use an acceptable method of contraception (as described in section 3.4.1) to avoid pregnancy for the duration of the trial and for 1 week after the last dose of trial medication. 10. Current participation in another clinical trial of a device, interventional medicinal product, advanced therapy, or surgical procedure; or previous participation within 6 months of the screening visit. 11. Any medical condition or previous treatment which in the investigator’s opinion compromises the potential participant’s ability to participate. *Patient’s must not have taken a Sodium-Glucose Transport Protein 2 (SGLT2) inhibitor within 24 hours before the screening visits to be eligible for the trial. 2026-02-28T00:00:00.000Z 2027-05-31T00:00:00.000Z Chronic urinary tract infection Urological and Genital Diseases Participants will be recruited and randomly allocated (via an online web-based randomisation service called Sealed Envelope) to one of two treatment arms in a 1:1 ratio: Arm A (Experimental): Treatment dose antibiotic in combination with methenamine hippurate Arm A includes treatment with one of three treatment dose antibiotic options, selected by the treating clinician, in combination with methenamine hippurate. Participants allocated to this arm will receive combination therapy, consisting of one of the following antibiotics: 1. Cefalexin (500 mg four times daily), or 2. Nitrofurantoin (100 mg twice daily), or 3. Trimethoprim (200 mg twice daily) in combination with Methenamine Hippurate (1 g twice daily) for 12 weeks. Arm B (Active Comparator): Prophylactic dose antibiotic or methenamine Hippurate monotherapy Arm B includes treatment with one of four prophylactic dose antibiotics or methenamine hippurate, but not both, selected by the treating clinician. Participants in this arm will receive monotherapy of one of the following: 1. Amoxicillin (250 mg once daily), or 2. Cefalexin (125 mg once daily), or 3. Nitrofurantoin (50 mg once daily), or 4. Trimethoprim (100 mg once daily), or 5. Methenamine hippurate (1 g twice daily) for 12 weeks. All treatment will be taken orally. Participants will be followed up every 4 weeks while taking trial medication. Drug Phase II Amoxicillin, nitrofurantoin, cefalexin, trimethoprim, methenamine hippurate Data sharing statement to be made available at a later date 7a3f9b49-535c-4cff-b779-1a863113866e 5c5689fe-7d02-428e-9c8c-b65f96b8fcdf 5b1cdf03-20bc-4436-be9e-93cf67bf4aa0 9fa573e6-5534-49cf-b871-98f934bd528a No Rajvinder Khasriya Scientific Principal investigator

Pond Street

London United Kingdom NW3 2QG - r.khasriya@ucl.ac.uk Public EAT-UP Trial Team Public

Comprehensive Clinical Trials Unit 90 High Holborn

London United Kingdom WC1V 6LJ - cctu.eat-up@ucl.ac.uk Public University College London Comprehensive Clinical Trials Unit University/education Non-commercial Medical Research Council http://dx.doi.org/10.13039/501100000265 10591726 true AMELIE: European, multicentre, single-arm (Phase I) trial of autologous skeletal muscle-derived cell microcarrier combination for the treatment of faecal incontinence in women with obstetric anal sphincter injury AMELIE Current study objectives as of 10/03/2026: The co-primary objectives of the trial are: 1. To determine the safety of the autologous skeletal muscle-derived cell (ASMDC)-PLGA microcarrier treatment within the 12 months post-treatment. 2. To determine whether treatment with ASMDC-PLGA microcarriers leads to a clinically relevant reduction in how often patients experience episodes of faecal incontinence. The two secondary objectives of the trial are: 1. To determine treatment impact on quality of life. 2. To determine the cost-benefit profile of the treatment. Previous study objectives: The co-primary objectives of the trial are: 1. To determine the safety of the autologous skeletal muscle-derived cell (ASMDC)-PLGA microcarrier treatment within the 6 months post-treatment. 2. To determine whether treatment with ASMDC-PLGA microcarriers leads to a clinically relevant reduction in how often patients experience episodes of faecal incontinence. The two secondary objectives of the trial are: 1. To determine treatment impact on quality of life. 2. To determine the cost-benefit profile of the treatment. Background and study aims Faecal incontinence (FI) is a public health problem with a big impact on people’s quality of life. Women who have given birth form a significant proportion of this patient group, as tears to the perineum during childbirth can lead to faecal incontinence. This study will test the safety of a cell-based therapy in women with post-obstetric faecal incontinence. Who can participate? Female patients aged 18 years and over with chronic faecal incontinence and a history of obstetric anal sphincter injury. What does the study involve? Surgeons will take a muscle biopsy from the patient's chest. This biopsy will be processed to grow muscle cells, which are combined with small porous carrier particles called microcarriers. The combination cell-microcarrier product will be injected into the patient’s external anal sphincter, leading to muscle regeneration. All the patients will receive the same treatment and all the patients and their doctors are aware of the treatment. The researchers will assess the safety of treatment. Researchers will also look at the number of FI episodes participants experience, and will record other patient-reported outcomes to find out how well the treatment works. When looking at this, researchers will compare data collected during the patient’s initial visits with data collected 12 months after treatment. Participants will take part in 11 visits. What are the possible benefits and risks of participating? The treatment used is an experimental product so it has not yet been authorised/marketed for use by the general public. As this study is a ‘first-in-human’ usage, there is no data to show its safety. The researchers have reviewed all previous studies of ASMDC (cells without microcarriers). In these studies, which involved a total of 615 patients (in 14 studies), the risks of treatment with cells alone were small. The risks were almost entirely related to the biopsy and injection procedures: Pain or skin irritation: approx. 1 in 10 (10%) Minor bruising: approx. 1 in 20 (5%) Superficial infection: <1 in 20 (<5%) Muscle weakness at biopsy site: <1 in 100 (<1%) Bleeding requiring surgical intervention: 1 reported in 615 Complications of routine anaesthesia: No occurrences. Typical risk is <1 in 1000. Since PLGA microcarriers are a newer treatment, we don’t have studies like this on their safety in treating faecal incontinence. The study team has also done tests in laboratories to check the risks of treatment, and the results have been acceptable. There are also several commercially available products which have been approved for clinical use which use microcarriers in products that are injected into the body. Muscle biopsy: It is inevitable that some pain will be experienced during the procedure due to the injection of the local anaesthetic and possibly the biopsy itself. There may also be some pain after the procedure. Potential risks include bruising, haematoma (a clot of blood), infection, delayed wound healing and a small amount of scarring. Participants may be provided with simple analgesics as needed. Product injection: Potential side effects include bleeding, infection, inflammatory response or irritation, pain or discomfort, worsening incontinence, diarrhoea, constipation, blockage of the intestine or faecal retention. There is also a small risk of allergic response to the contents of the product (cells or components of the final formulation), and infection. This is expected to be minimal because the product is made from the participant’s own cells. Because this study involves an experimental treatment, not all risks and outcomes can be predicted. There may be some risks that the study doctors are not currently aware of. It is possible that some of these unknown risks could be permanent, serious, or life-threatening. Participant safety will be monitored throughout the trial. Oversight committees (and where appropriate, regulators) will be kept informed of trial safety. Stopping rules will trigger study stop if accruing data indicates a safety concern. Patients will be provided with a safety card containing contact details of the study team, which they can use to ask questions about the study, or if they are experiencing pain or discomfort and want advice. There is a chance of product delivery failure. This could happen for a number of reasons, including but not limited to delays to the courier, problems with temperature control, or issues when making the product, which could mean the trial treatment isn’t safe to use. Should the risk occur, where time and resources allow, participants will be offered a second round of muscle biopsy and treatment. Participants may find trial involvement or questionnaire/ diary completion burdensome. Clinical trial involvement could affect participants’ insurance cover. This research study may have unknown risks for a pregnancy, and nursing infants. People who are breastfeeding/ pregnant/ planning to become pregnant cannot participate in the study. Pregnancy testing will be performed, and the use of effective contraception methods will be required for people of child-bearing potential. Should patients become pregnant during the trial, they will be withdrawn from the trial or monitored (according to whether the treatment has yet been administered). Administered drugs: A small chance of reaction or allergy to antibiotics and other drugs used. Endoanal ultrasound, anorectal manometry, sigmoidoscopy: Small chance of soreness or minor bleeding afterwards and a negligible (<1/10,000) possibility of perforation or damage of the intestinal wall. Blood testing: Risk of bleeding, discomfort, light-headedness, pain, bruising, and rarely, an infection at the puncture site. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? December 2025 to August 2027 Who is funding the study? Horizon 2020 Who is the main contact? Dr Josephine Parker, cctu.amelie@ucl.ac.uk 1. The incidence of ATIMP-related or ATIMP administration procedure-related adverse events associated with the use of ASMDC-PLGA microcarriers within 12 months post-treatment (safety endpoint of primary hypothesis and outcome is reported at 12 months) 2. Estimate of a minimum clinically relevant reduction in the frequency of total FI episodes measured using participant bowel diaries at 12 months compared to baseline levels 1. Quality of life assessed using patient questionnaires: Resource Use Measure, EQ-5D-5L, mean cost of healthcare resource use per patient 2. Additional clinical efficacy outcomes will be assessed using patient questionnaires: St Mark’s Incontinence Score; Likert scale of patient’s global impression of treatment success; Short-Form Bowel Symptom Importance Questionnaire (SF-BSIQ); Measure Yourself Medical Outcome Profile All secondary outcome measures are evaluated at baseline (visit 3), and 3 and 6 months after treatment (visit 9 and 10). Where patients take part in extended follow-up, data collection will take place at visits 11 and 12 (12 and 18 months after treatment). Exceptions: Likert scale not evaluated at visit 3 EQ-5D-5L collected at visit 6 (day of treatment). Resource Use Measure not collected at visit 9 (3 months) Ethics approval required South Central - Berkshire B Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/SC/0387 10.1186/ISRCTN10591726 1007874 CPMS: 58948, CTU/2018/324 1007874 58948 CTU/2018/324 Single-arm trial first in human Interventional Non randomised study Safety 2027-08-31T00:00:00.000Z United Kingdom England Wales Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital of Wales

Heath Park

Cardiff England CF14 4XW R2F2E@2.16.840.1.113883.2.1.3.2.4.18.48 Patient false 1. Female patients aged ≥18 years 2. Chronic faecal incontinence 3. History of obstetric external anal sphincter injury 4. Non-surgical treatments for faecal incontinence have been attempted to applicable national standards 5. Minimum severity: 8 faecal incontinence or urgency episodes in 4-week screening period, with a minimum of 4 episodes of faecal incontinence Mixed 18 Years 100 Years Female 12 0 1. Patients within 1 year of acute sphincter injury 2. Patients who have undergone previous anal reconstructive surgery 3. Other gastro-intestinal diseases (see protocol for details) 4. Pregnancy or intent to become pregnant during trial 5. Morbid obesity (BMI ≥35 kg/m2) 6. Certain comorbidities (recent history of cancer, systemic neuromuscular and connective tissue diseases, transmissible viral infection) 7. Patient currently using sacral neuromodulation (SNM) or has failed SNM implant for faecal incontinence; failed test stimulation phase is permitted 8. Patient has positive virology or parasitology results (Hepatitis B, C & E, HIV 1 & 2, syphilis, human T-lymphotropic virus I or II, Epstein-Barr virus, Cytomegalovirus, Toxoplasma gondii, Trypanosoma cruzi, West Nile Virus or malaria) confirmed, where appropriate, using local testing policies. Note T. cruzi, malaria and West Nile Virus tests only required if relevant participant history criteria met. 2025-12-15T00:00:00.000Z 2026-02-13T00:00:00.000Z Faecal incontinence (FI) in women with obstetric anal sphincter injury Digestive System Advanced therapy medicinal product – cell-based ASMDC-PLGA microcarriers [Poly(DL-lactide-co-glycolide) (PLGA) microcarriers combined with autologous skeletal muscle cells (ASMDC), derived from the skeletal muscle biopsy All participants will undergo surgery to obtain a muscle biopsy from the pectoralis major muscle. Following successful product preparation, all will receive a one-off injection of autologous skeletal muscle derived cell (ASMDC) PLGA microcarrier combination treatment into the external anal sphincter. After injection, the patient will be followed up with safety checks, which will continue for 12 months after treatment. Biological/Vaccine Phase I ASMDC-PLGA microcarriers [Poly(DL-lactide-co-glycolide) (PLGA) microcarriers combined with autologous skeletal muscle cells (ASMDC), derived from the skeletal muscle biopsy The data that support the findings of this study are not openly available and anonymised data could be requested and would require approval in writing where appropriate, after formal application to the TMG and CCTU. Available on request 60bb3a2e-6dc9-43e1-8b76-47cb6095f8b0 5e3a4610-05d9-418a-a88b-6c2818f058b0 8130a3a7-63ac-4d30-a165-4dbb099ab859 f726b122-9166-427b-94ce-35a464ec9608 Yes Josephine Parker Scientific

Gower Street

London United Kingdom WC1E 6BT +44 (0)207 670 4845 cctu.amelie@ucl.ac.uk Public Charles Knowles Principal investigator

327 Mile End Road

London United Kingdom E1 4NS - c.h.knowles@qmul.ac.uk Public University College London University/education https://ror.org/02jx3x895 Non-commercial Horizon 2020 http://dx.doi.org/10.13039/501100007601 21516608 true A randomised multiple centre trial of conservative versus liberal fluid administration for children receiving a kidney transplant LIMITS A relative limitation of fluid volume administered to children receiving kidney transplant is superior to usual liberal fluid volume administration in terms of days at home to 30 days after transplant. Background and study aims Kidney transplantation is the treatment of choice for children with established kidney failure. Children having a kidney transplant receive fluid by a drip, both during and after the operation. The best amount of fluid for children with a new transplant is not known. Too little fluid can cause delays in the kidney transplant working, or blood clots in the transplant. Too much fluid can cause breathing difficulties, swelling, high blood pressure, headaches or fits. These problems are important to patients and take up valuable specialist NHS resources. There is a pressing need to work out the best amount of fluid for children having a kidney transplant. We are a group of kidney doctors, surgeons, a psychologist, parents, young people and trial experts working together on the LIMITS research study to answer this question. Our aim is to find out whether children having kidney transplants should have a limited amount of fluid given according to their body size, or the larger volumes of fluid that are usually given. Following input from parents and young people a key aim of this research is helping children spend more time at home after transplant. This study will help to work out the best amount of fluid for children after kidney transplant. This could speed up children’s recovery, improve their experience of transplant and free up specialist NHS resources. It therefore has the potential to change clinical practice and importantly improve the treatment and outcomes of children receiving kidney transplants in the UK. We will publish the results in a widely read medical journal and present them at conferences and on the study website. Who can participate? Any child or young person who is receiving a kidney-only transplant from either a living or deceased donor in a participating UK centre may participate. The child or young person must be under the age of 18 years at the time of kidney transplantation. What does the study involve? The study will compare recovery in children having different amounts of fluid after kidney transplant. Some children will receive the large amounts that doctors usually give. For others, we will limit the amount of fluid given according to their body size. An independent process called randomisation will decide which fluid amount each child receives. The fluid will be given through a vein (intravenously), by mouth (enterally) or by the child’s usual route. All transplant recipients are given intravenous fluids or enteral fluids during their admission, so this is not an additional burden for trial participants. There will be no study specific blood samples and no extra study visits beyond routine clinical follow up. Blood tests will be done as per standard care with options for mild topical anaesthetics and use of distraction techniques. We will assess children's recovery by the number of days spent at home (rather than in hospital) after transplant. We will work out the impact on health and health service costs from limiting fluid compared to usual practice. We hope that 140 children from the 10 UK children’s kidney transplant hospitals will take part over 2 years. This number is calculated to ensure that the study is large enough to reach a firm conclusion. Children who agree to join the study will be split into 2 equal groups. Depending on what group the child is in, they will receive either usual amounts of fluid, or a limited amount of fluid tailored to their body size. We will ask children and parents to report their symptoms and experience of their transplant hospital stay. What are the possible benefits and risks of participating? Possible benefits: Research participants may experience less unpleasant symptoms from fluid overload (i.e. less swelling, shortness of breath, headache and fits) and subsequently avoid further intervention to investigate and treat these symptoms which could be uncomfortable or cause psychological distress (i.e. additional medications, blood transfusion, oxygen, additional investigations such as chest x-ray). They may potentially go home earlier after kidney transplant so spend less time in hospital. Possible Risks: There are few risks to taking part in this trial, above the risk of kidney transplantation itself. The key risks of liberal fluid administration (current majority practice) are related to fluid overload and are: • high blood pressure which can lead to headaches and seizures • fluid on the lungs (pulmonary oedema) which can lead to difficulty breathing • electrolyte disturbance which can lead to fits (seizures) • increased blood transfusions • unexpected intensive care or high dependency unit admission Some clinicians expressed concern about delayed transplant function and/or thrombosis with a capped fluid approach but this risk is not evidenced-based. Observational data in paediatric kidney transplant recipients <20kg have shown favourable outcomes with less liberal intra-operative fluid volume administration. There is no evidence base for the current liberal use of fluid. These risks will be mitigated by frequent monitoring of clinical observations. If identified, prompt investigation and treatment will be commenced. This practice will be followed in both arms of the clinical trial. In summary, the risks of participating in the study are not felt to be greater than those of standard clinical care. Where is the study run from? Great Ormond Street Hospital for Children NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? January 2025 to December 2027 Who is funding the study? National Institute for Health and Care Research (UK) Who is the main contact? Dr Wesley Hayes, chief investigator, Wesley.Hayes@kispi.uzh.ch Dr Nuala Calder, clinical research fellow, n.calder@ucl.ac.uk Dr Fotini Kaloyirou, trial manager, fotini.kaloyirou@nhsbt.nhs.uk Mean days at home in the first 30 days after kidney transplant measured using patient records 1. Patient-reported experience of transplant hospital stay (from admission to discharge) 2. Proportion of participants with systemic hypertension (systolic blood pressure above the 95th centile for age and height on 2 consecutive days) within 7 days after transplant 3. Proportion of participants with pulmonary oedema on chest x-ray within 7 days after transplant 4. Proportion of participants with severe acute hyponatraemia (plasma sodium concentration <130mmol/l) within 7 days after transplant 5. Proportion of participants receiving a red blood cells within 7 days after transplant 6. Proportion of participants with transplant thrombosis in the post-operative period leading to graft failure within the first 30 days 7. Proportion of participants with delayed transplant function (dialysis within the first 7 days after transplant) 8. Mean transplant function measured by estimated glomerular filtration rate at 3 months post-transplant 9. Cost-effectiveness analysis: kidney-related costs within the study period (all costs incurred and implications for patient health within the study.) Ethics approval required Cambridge South REC

The Old Chapel Royal Standard Place

Nottingham United Kingdom NG1 6FS 25/EE/0161 10.1186/ISRCTN21516608 354370 CPMS: 69346, NIHR: 206591 354370 69346 206591 A pragmatic multicentre open label randomized controlled trial with internal pilot phase and integrated economic evaluation Interventional Randomised controlled trial Efficacy Treatment 2027-12-31T00:00:00.000Z United Kingdom England Northern Ireland Scotland Great Ormond Street Hospital for Children

Great Ormond Street

London England WC1N 3JH Evelina London Children's Hospital

Westminster Bridge Road

London England SE1 7EH Bristol Royal Hospital for Children

Paul O'Gorman Building Upper Maudlin Street St Michael's Hill

Bristol England BS2 8BJ Birmingham Childrens Hospital

Steelhouse Lane St. Chads Tunnel

Birmingham England B4 6NH Royal Manchester Childrens Hospital

Oxford Road

Manchester England M13 9WL Leeds Children's Hopsital

Clarendon Wing Leeds General Infirmary

Leeds England LS1 3EX Royal Hospital for Sick Children (Glasgow)

1345 Govan Road

Glasgow Scotland G51 4TF Great North Children's Hopsital

Victoria Wing Royal Victoria Infirmary

Newcastle upon Tyne England NE1 4LP Nottingham Children's Hospital

Queen's Medical Centre, Derby Road Lenton

Nottingham England NG7 2UH The Royal Belfast Hospital for Sick Children

274 Grosvenor Road

Belfast Northern Ireland BT12 6BA University Hospital of Wales

Heath Park

Cardiff Wales CF14 4XW RWMBV@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 Alder Hey Children's NHS Foundation Trust

Alder Hey Hospital Eaton Road West Derby

Liverpool England L12 2AP RBS25@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Children under 18 years of age at the time of transplantation with valid informed consent 2. Children receiving a kidney only transplant from either a living or deceased donor, in a participating UK centre Mixed 0 Months 18 Years All 140 0 Multi-organ transplant recipients 2025-10-23T00:00:00.000Z 2027-06-30T00:00:00.000Z Fluid management in paediatric kidney transplantation Surgery Summary of treatment in each group: - Intervention: Fluid volume administration capped at maximum 150ml/m²/hour for no longer than 18 hours following transplant, reduced to a fixed daily target of maximum 1.5 litres/m²/day thereafter. No specific urine output will be targeted. No diuretics to be administered throughout. - Comparator: Target urine output >2ml/kg/hour. Fluid administered to replace urine output + insensible losses for at least 48 hours. Diuretics per the clinical team’s usual practice. Follow up period: Follow up data up will be collected up to 3 months post-transplant. Randomisation: Eligible patients who have consented to participate in LIMITS will be randomised via an interactive web response system, provided by Sealed Envelope. Participants will be randomised in a 1:1 ratio, to the intervention and comparator groups. The randomisation will be stratified by transplant centre and donor type (deceased vs. living donation). Randomisation will further be balanced within blocks of varying, undisclosed sizes. Other The datasets generated during and/or analysed during the current study are/will be available upon request from NHSBT Clinical Trials Unit (ctu@nhsbt.nhs.uk). The type of data: fully anonymised analysis dataset. When the data will become available and for how long: 9 months after publication and ending 5 years following article publication. By what access criteria data will be shared including with whom: Data will be shared with investigators whose use of the data has been assessed and approved by an NHSBT review committee and the Sponsor as a methodologically sound proposal. A full Data Sharing Request form will be required. For what types of analyses, and by what mechanism: to be agreed before data is shared Whether consent from participants was obtained: Data of participants who have not agreed to the use of their data for future research, will be removed from the dataset. Comments on data anonymisation: data will be anonymised prior to sharing. Any ethical or legal restrictions: none. Any other comments: a contract is mandatory before any data is shared with a third party. Available on request 2026 Protocol article in https://pubmed.ncbi.nlm.nih.gov/42270097/ (added 11/06/2026) Protocol

Migrated from study website field

7ba4dc8c-03a8-45f7-8519-aeebc0a6dc2c e48ae550-5cfa-4e48-b737-80d5e504f4b1 357fcb6c-cbdc-48d3-a0f0-6e8f78eb3f5a 889f16f3-7e8b-45ec-9193-f85adada9023 99e1f6fa-249e-495f-891e-95d97ab1886b Yes Wesley Hayes Scientific Principal investigator

Great Ormond Street Hospital

London United Kingdom WC1N 1EH +41 78 326 1236 Wesley.Hayes@kispi.uzh.ch Public Fotini Kaloyirou Public

NHSBT CTU Long Road

Cambridge United Kingdom CB2 0PT +44 7385388072 fotini.kaloyirou@nhsbt.nhs.uk Public Nuala Calder Scientific

Bristol Royal Hospital for Children, Paediatric Nephrology Department, Upper Maudlin Street

Bristol United Kingdom BS2 8BJ +44 7385388072 n.calder@ucl.ac.uk Public Great Ormond Street Hospital for Children NHS Foundation Trust Hospital/treatment centre https://ror.org/03zydm450 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 87163290 true Baricitinib in Juvenile Dermatomyositis (BAR-JDM): A multi-centre, open label, randomised, controlled, superiority, Bayesian, phase 3a trial comparing baricitinib and glucocorticoids to methotrexate and glucocorticoids over 52 weeks BAR-JDM The main objective is to determine efficacy and safety of baricitinib in combination with steroids (glucocorticoids) compared with methotrexate and glucocorticoids in children with newly diagnosed juvenile dermatomyositis. Efficacy is determined by meeting the primary endpoint: Proportion of participants achieving clinically inactive disease which is assessed using a criteria known as the modified PRINTO criteria, at the end of the trial (Week 52) AND off steroids (glucocorticoids) from Week 40. Safety is measured by how many side effects, also called adverse events, are reported by the participants. Secondary objectives of this trial are related to: - how many people in the baricitinb group had their medication dose increased - how many participants achieved clinically inactive disease as determined by clinicians - information on steroid (glugocorticoids) taken by participants, including the total dose of steroids taken - how many people had rescue treatment (medications to help them get better) throughout the trial - Participants disease state as determined by clinician assessments - Side effects reported - How many patients have disease flares - Health-related quality of life, functional ability and disease activity as reported by the participant/their parent/legal representative - Healthcare resource use and health-related quality of life for health economics analysis Background and study aims Juvenile dermatomyositis (JDM) is a rare inflammatory disease affecting muscles, skin, and blood vessels, with an annual incidence of about 3 per 100,000 children. Standard treatment uses high dose steroids (glucocorticoids) and immunosuppressants (like methotrexate (MTX)) which dampens the body’s immune system. This treatment only works in some people to control the disease, so doctors are looking at other medicines that could be more effective and have less side effects. Baricitinib is used in adults with rheumatoid arthritis and children with arthritis. It works by targeting an intracellular signalling pathway called “JAK-STAT”, which may provide a more targeted way of reducing inflammation. The aim of this trial is to find out if baricitinib and steroids is better and safer compared to MTX and steroids in the treatment of children with newly diagnosed JDM. Participating NHS hospital sites across the UK will recruit 30 participants aged 2 years to less than 17 years. Who can participate? Patients aged 2 to 17 years with newly diagnosed juvenile dermatomyositis (JDM) who have not had any treatment for it. What does the study involve? There will be two groups: one group will receive baricitinib tablets and one group will receive MTX injections which they will take for 52 weeks. Participants will randomly be put into the group; they don't get to choose. Participants in the baricitinib group may have their dose increased. All participants will take steroids, with doses gradually reduced. There will be twice as many people taking baricitinib than MTX as more information is known about the standard treatment. Rescue treatment can be given at any time in the trial following local practices. After attending a Screening visit, participants eligibility will be confirmed at a Baseline and Randomisation visit. Progress will be checked at participants local research hospital at Week 12, 24, 39, and 52, where questionnaires, assessments, and blood/urine tests are completed. There is an end of trial visit which may be a call or clinic visit. What are the possible benefits and risks of participating? Risk mitigation measures added to the protocol to address the important potential risks include appropriate inclusion and exclusion criteria, safety monitoring, study drug interruption, and permanent discontinuation criteria. Infections are common side effects of the medication studied. The non-serious infections noted in a rheumatoid arthritis (RA) program (upper respiratory tract infections, herpes zoster, herpes simplex) are readily diagnosed, manageable, and typically resolve without long-term sequelae. Prior to receiving baricitinib, the vaccination status of patients must be up to date with all immunisations and follow the local requirements for vaccination guidelines for immunosuppressed patients. Exclusion criteria have been added to the protocol to limit enrolment of patients who are at increased risk of infection. Hepatotoxicity has not been identified with baricitinib use, but increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin have occurred in RA patients treated with baricitinib. Most increases improved with continued use or temporary discontinuation of baricitinib with no long-term effects. In addition to criteria to exclude patients with liver failure or increased liver analytes, appropriate monitoring of hepatic analytes and discontinuation criteria have been included in the protocol. Effects of baricitinib on human foetal development are not known. The study protocol excludes pregnant and breastfeeding participants. Contraceptive use is required for participants who may become pregnant or cause pregnancy, i.e. women of childbearing potential and fertile men. Venous thromboembolic events (VTEs) including deep vein thrombosis (DVT) or pulmonary embolism (PE) have been determined to be an important potential risk for baricitinib. There was a numerical imbalance in reports of VTEs in a 24-week placebo-controlled period of the Phase 3 studies of adult patients with RA. Available evidence does not establish a causal association. The exposure-adjusted incidence rate of VTE for baricitinib-treated RA patients over long-term exposures was similar to the background rates published in the literature for the target population. There was no pattern of increased or decreased risk during long-term exposures, and cases observed with baricitinib were confounded by one or more recognised risk factors for VTE. VTE risk can be managed through risk-mitigation strategies. Exclusion and discontinuation criteria have been added to the protocol to limit participation of patients who are at increased risk of VTE. Baricitinib is being used to treat paediatric patients participating in an expanded access program ( see protocol) with over 30 patients aged 2 months to <18 years were enrolled in the program. Safety information has not identified new safety signals for baricitinib beyond those known. As children generally have fewer age-related comorbidities, such as diabetes and heart disease, they are expected to be at a lower risk for some AEs related to comorbidities observed in RA studies and are not anticipated to be at any higher risk of AEs potentially associated with baricitinib. Therefore, based on the efficacy of baricitinib demonstrated in the Phase 3 RA program and the observed safety profile, the probability of a positive benefit/risk warrants this study to be conducted, given the unmet need in patients with JDM. More information about the known and expected benefits, risks, SAEs and reasonably anticipated AEs of baricitinib is found in the Summary of Product Characteristics (SmPC). Children with JDM do not respond satisfactorily after treatment with glucocorticoids in combination with methotrexate, or do not tolerate these drugs. Attempts with other immunosuppressive agents in these group of patients have been disappointing, and these patients may continue to deteriorate with progressive muscle weakness and impaired function in daily activities. There is no guarantee that baricitinib treatment will be efficacious, but no other alternatives are licensed. Thus, there will be considerable benefits for patients with JDM, if they could improve with baricitinib treatment. The benefits of treatment far outweigh both the risk of adverse events, which may also occur with other combinations of immunosuppressive drugs, and the risk that the drug is not effective. The knowledge gained from this study may also be of help to other participants in the future. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? The grant started in June 2024 and recruitment is expected to open in March 2024. The trial will end in June 2029. Who is funding the study? Versus Arthritis (UK) Who is the main contact? cctu.bar-jdm@ucl.ac.uk The primary endpoint is the proportion of participants achieving clinically inactive disease, as per modified PRINTO criteria, at Week 52 AND off glucocorticoids from Week 40. Clinically inactive disease as per modified PRINTO criteria is achieved if a participant fulfils the following criteria: a. No active skin disease, and b. Physician global assessment (PhyGLOVAS) ≤0.2/10 on a visual analogue scale, and c. Two of the following three criteria: i. Creatine kinase (CK) ≤150 U/L. ii. Childhood Myositis Assessment Scale (CMAS) ≥48/52. iii. Manual Muscle Testing 8 (MMT8) ≥78/80. 1. Proportion of participants requiring protocoled baricitinib dose escalation at Week 12 or Week 24. 2. Proportion of participants achieving clinically inactive disease and off glucocorticoids from Week 25. 3. Proportion of participants achieving clinically inactive disease at Week 52 but received prednisolone beyond Week 25. 4. Proportion of participants requiring rescue treatment. 5. Cumulative dose of prednisolone (mg/kg) at trial end. 6. Cumulative dose of methylprednisolone (mg/kg) at trial end. 7. Time to clinically inactive disease (see Appendix 1 of protocol for definition) following the protocoled glucocorticoid tapering schedule. 8. Number of grade 3 to 5 adverse events (AEs), including deaths, and serious adverse events (SAEs) reported. 9. Toxicity of glucocorticoids as assessed by the paediatric glucocorticoid toxicity index. 10. Proportion of patients with disease flares defined as worsening disease after clinically inactive disease as assessed at the time of trial visits within 52 weeks. 11. Cumulative weight adjusted dose of prednisolone or methylprednisolone received. 12. Duration of glucocorticoid treatment from the Baseline and Randomisation visit. 13. JDM Paediatric Rheumatology International Trials Organisation (PRINTO) 20, 50, 70, and 90 levels of improvement (20%, 50%, 70%, and 90% improvement from the Baseline and Randomisation visit in three of six core set variables at a given visit with one or no variable worsening by more than 30% (muscle strength excluded)) at Weeks 12, 24, 39 and 52, with adherence to glucocorticoid schedule. 14. Minimal clinical response according to the International Myositis Assessment and Clinical Studies (IMACS) Group criteria at Weeks 12, 24, 39 and 52, with adherence to glucocorticoid schedule (Web calculator for 2016 ACR/EULAR Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis (nih.gov)). 15. Total improvement score at Week 12, 24, 39 and 52, with adherence to glucocorticoid schedule (Web calculator for 2016 EULAR/ACR Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis (nih.gov)). 16. Health-related quality of life (Physical Summary Score of the Child Health Questionnaire - Parent Form 50 (CHQ-PF50) and Paediatric Quality of Life Inventory (PedsQL)), functional ability (Childhood Health Assessment Questionnaire (CHAQ)) and disease activity (patient/parent global activity Visual Analogue Score (VAS)) evaluation at the Baseline and Randomisation visit, Week 12, 24, 39 and Week 52 visit. 17. Healthcare resource use and health-related quality of life (Child Health Utility 9D (CHU-9D)) for use in health economics analysis at the Baseline and Randomisation visit, Week 24 and Week 52 visit. Ethics approval required West Midlands - Edgbaston Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/WM/0037 10.1186/ISRCTN87163290 1011391 CPMS: 67281, CTU/2023/432 1011391 67281 CTU/2023/432 Interventional open-label randomized parallel-group controlled trial Interventional Randomised parallel trial Efficacy Safety 2029-06-02T00:00:00.000Z United Kingdom England Scotland Great Ormond Street Hospital

Great Ormond Street

London England WC1N 3JH RJ232@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Hospital for Sick Children (Glasgow)

1345 Govan Road

Glasgow Scotland G51 4TF G513H@2.16.840.1.113883.2.1.3.8.2.16.2 Alder Hey Children's Hospital

E Prescot Rd

Liverpool England L14 5AB Evelina London Children's Hospital

Westminster Bridge Road

London England SE1 7EH Manchester Royal Infirmary

Cobbett House Manchester Royal Infirmary Oxford Road

Manchester England M13 9WL RW301@2.16.840.1.113883.2.1.3.2.4.18.48 Southampton Children's Hospital

Tremona Road

Southampton England SO16 6YD Cambridge University Hospital

Hills Road

Cambridge England CB2 0QQ Leeds Children's Hospital

Clarendon Wing

Leeds England LS1 3EX Great North Children's Hospital Newcastle

Victoria Wing Royal Victoria Infirmary

Newcastle upon Tyne England NE1 4LP Nottingham Children's Hospital

Derby Road Lenton

Nottingham England NG7 2UH Birmingham Children's Hospital

Steelhouse Lane

Birmingham England B4 6NW RTH39@2.16.840.1.113883.2.1.3.2.4.18.48 Bristol Royal Hospital for Children

Paul O'Gorman Building Upper Maudlin Street St Michael's Hill

Bristol England BS2 8BJ 11HAG@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Patients with newly diagnosed (treatment naïve) juvenile dermatomyositis (JDM) who meet European League Against Rheumatism (EULAR)/ American College of Rheumatology (ACR) classification criteria for possible, probable or definite JDM; or modified (i.e. incorporating MRI muscle findings in place of EMG) Peter and Bohan criteria for possible, probable or definite JDM. 2. Active disease for JDM using the following pre-specified definition: a. Active inflammatory disease based on persisting or worsening muscle weakness (for example, Manual Muscle Testing 8 (MMT8) <78/80 or CMAS <49/52), and b. At least one other sign of active disease: i. Elevated serum levels of at least one muscle enzyme (creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT)) above upper limit of normal and being explained by muscle involvement and no other cause such as liver disease, or ii. Inflammation in recent (<12 weeks) muscle biopsy or MRI scan, or iii. Active extra muscular disease: dermatomyositis-specific skin rash, arthritis, or interstitial lung disease (ILD) as suggested by chest x-ray or high-resolution computerised tomography (HRCT) or pulmonary function test. 3. Participants aged ≥2 years to <17 years at the Baseline and Randomisation visit. 4. Written informed consent from: a. Participants who have reached the age of consent (16 years), or b. Parent/legal representative of participants who have not reached the age of consent (16 years); and assent, where possible, from the participant. Child 2 Years 17 Years All 30 0 1. Participants with other types of inflammatory myopathies. 2. Participants where the use of baricitinib, methotrexate or glucocorticoids would be contraindicated, including known hypersensitivity or history of severe allergic reaction to any of the study medications or their excipients. 3. Participants who are pregnant or breastfeeding at the screening visit. 4. Participants of childbearing potential that are unwilling to have pregnancy testing done according to the protocol schedule for the duration on the trial. 5. Participants of childbearing potential or fertile men that are either considering becoming pregnant/having children or are unable/unwilling to use an acceptable method of contraception to avoid pregnancy for the duration on the trial and for 6 months after the last dose of trial medication. 6. Participants who have an active varicella zoster infection (chickenpox) or have had exposure to a case of varicella (chickenpox or shingles) within 21 days of the screening visit. 7. Participants who have active herpes zoster that resolved within 8 weeks of the screening visit. 8. Participants who have a serious systemic or local infection or who have had a serious systemic or local infection within 12 weeks of the screening visit. 9. Participants who have received live/attenuated vaccines in the 4 weeks prior to screening or who plan to receive live/attenuated vaccines for the duration on the trial. 10. Participants with a history of active hepatitis B, hepatitis C or human immunodeficiency virus. 11. Participants with evidence of active or latent tuberculosis. 12. Participants with any of the following laboratory values at screening: a. Haemoglobin (Hb) <80 g/L (alternative units <8 g/dL), or b. Absolute lymphocyte count (ALC) <0.5x109/L (alternative units <500 cells/mm³), or c. Absolute neutrophil count (ANC) <1x109/L (alternative units 1000 cells/mm³), or d. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m². 13. Any other clinical feature or laboratory test result that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this trial. 14. Current participation in another clinical trial of a device, interventional medicinal product, advanced therapy, or surgical procedure; or previous participation within 12 weeks of the screening visit. 15. Participants who have received > 3 g of intravenous methylprednisolone within 4 weeks prior to randomisation. 16. Participants who have received oral prednisolone/prednisone at a dose ≥2 mg/kg once daily for more than 4 weeks and completing the course in the 4 weeks prior to randomisation. 2025-07-01T00:00:00.000Z 2028-03-31T00:00:00.000Z Juvenile dermatomyositis (JDM) Musculoskeletal Diseases a. Trial arms: i. Experimental arm: Baricitinib and glucocorticoids    i. Control arm: Methotrexate and glucocorticoids (standard of care) b. Baricitinib: i. Dose range: Minimum 2mg to maximum 10mg. All participants on the baricitinib arm will start on a “lower” dose (2mg or 4mg) which is dependent upon their weight at the Baseline and Randomisation visit. At Week 12 and Week 24, if participants are clinically worsening or showing inadequate improvement, the baricitinib dose will be increased to a “higher” dose (6mg, 8mg, or 10 mg), dependent upon their estimated glomerular filtration rate and weight at that visit. ii. Dose frequency: Tablets to be taken once a day for first 12 weeks, then either twice a day or four times a day dependent upon dose for remainder of duration of treatment. iii. Route of administration: Oral (if children cannot swallow whole tablets, soluble form in water is acceptable). iv. Duration of treatment: 52 weeks (+/- 2 week protocol window). c. Methotrexate: i. Dose range: 15 mg/m2. Body weight, height, and body surface area will be assessed at every visit and used to determine methotrexate dosing and dispensing. ii. Dose frequency: Injection to be taken once weekly for duration of treatment. iii. Route of administration: Subcutaneous injection. iv. Duration of treatment: 52 weeks (+/- 2 week protocol window). d. Glucocorticoids (prednisolone): i. Dose range: All participants will receive the same protocolised oral prednisolone dosing regimen (and recommended non-mandatory supportive measures) starting from 2 mg/kg/day at the Baseline and Randomisation visit reducing to 0 mg/kg/day from Week 25. The Baseline and Randomisation body weight will be used to determine the glucocorticoid doses (prednisolone and methylprednisolone) for the duration of the trial. Maximum daily dose of oral prednisolone is 60 mg. ii. Dose frequency: Tablets to be taken once a day. iii. Route of administration: Oral (if children cannot swallow whole tablets, soluble form in water is acceptable). Intravenous methylprednisolone may be substituted for oral prednisolone at an equivalent (0.8 x prednisolone) dose at the discretion of the local investigator, if required for clinical or practical reasons. iv. Duration of treatment: First 24 weeks of treatment. e. Follow-up activity for all trial arms: After attending a Screening visit, participants eligibility will be confirmed at a Baseline and Randomisation visit. Progress will be checked at participants local research hospital at Week 12, 24, 39, and 52, where questionnaires, assessments, and blood/urine tests are completed. There is an end of trial visit which may be a call or clinic visit. f. Randomisation process: Participants will be randomised (2:1, baricitinib: methotrexate) using Sealed Envelope randomisation software customised for the trial by the UCL CCTU. Drug Phase III Baricitinib, methotrexate Applications for access to the trial dataset, at the end of the trial, can be submitted formally in writing to UCL CCTU and will be considered and approved in writing after formal consideration by the trial oversight committees and the Chief Investigator. Data, including sample data, collected may be shared with regulators and other researchers either at academic sites, nationally or internationally, or academic, commercial or charitable organisations approved by the Sponsor, in other future ethically approved research or regulatory approval process. Participants provide consent to their data being shared by signing the informed consent form. All relevant data sharing agreements will be in place. Available on request 92a2366c-30b8-4b43-a097-a07a4d444f79 07ccba41-bae2-4820-a4c5-7cfc5bf69df9 6808af2a-b596-4e41-b6ee-06d93c31e3c3 4baceb07-736a-41fb-ae58-448bac129bc6 0fd449b5-b30e-4ccb-b466-cc8f2c68be6d Yes Rachel McComish Public

Comprehensive Clinical Trials Unit at UCL 90 High Holborn

London United Kingdom WC1V 6LJ - cctu.bar-jdm@ucl.ac.uk Public Paul Brogan Principal investigator

UCL Great Ormond Street Institute of Child Health, 30 Guilford St

London United Kingdom WC1N 1EH - p.brogan@ucl.ac.uk Public Charalampia Papadoupoulou Scientific

Great Ormond Street Hospital, Great Ormond Street

London United Kingdom WC1N 3JH - charalampia.papadopoulou@gosh.nhs.uk Public University College London University/education https://ror.org/02jx3x895 Non-commercial Versus Arthritis http://dx.doi.org/10.13039/501100012041 61218504 true Phase I dose escalation and cohort expansion study to affirm the safety of pharmacological doses of a novel formulation of intravenous melatonin in babies with hypoxic-ischaemic encephalopathy (HIE) to augment therapeutic hypothermia (HT) treatment; to reduce the incidence and severity of disability in babies with moderate-severe HIE ACUMEN Primary objectives: 1. Safety profile assessment: to assess the safety profile of melatonin across all dose levels being studied based on the occurrence of dose-limiting events (DLE). 2. The attainment of putative therapeutic plasma melatonin levels (in the range of 15-30 mg/L) across dose levels being studied. 3. The attainment of putative ethanol safety (BAC levels <0.25 g/L) across dose levels being studied. 4. To identify the recommended Phase II dose (RP2D). Secondary objectives: 1. Pharmacokinetic (PK) model: to establish the pharmacokinetic (PK) profile of intravenous melatonin infusion in term infants with moderate to severe hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (HT). 2. Feasibility of neonatal neuroprotection trial network: to assess the feasibility of developing a neonatal neuroprotection trial network for future Phase II randomised controlled trials (RCTs) that will evaluate efficacy. 3. Recruitment feasibility: to assess the feasibility of recruiting participants within 6 hours of birth. Background and study aims The ACUMEN trial is a research study aimed at improving treatments for newborn babies with a condition called hypoxic-ischemic encephalopathy (HIE). HIE is a type of brain injury that occurs when a baby does not receive enough oxygen and blood flow around the time of birth. While cooling therapy (therapeutic hypothermia) is currently the standard treatment, many babies still experience long-term challenges, including developmental delays and learning difficulties. This study will test the safety and potential benefits of a drug called melatonin. Melatonin, a naturally occurring hormone, has shown promise in protecting brain cells in preclinical studies. The drug will be tested in its intravenous (IV) form to see if it can reach effective levels in the blood safely and tolerably for newborns. Who can participate? Babies with HIE who have been admitted to NICU What does the study involve? Participants will receive the drug alongside standard cooling therapy. The study drug will be given as an IV infusion over six doses (one loading and five maintenance doses) over a 72-hour period. Babies will be closely monitored during their hospital stay to ensure their safety and evaluate the drug’s effects. Blood samples (for melatonin, ethanol and biomarker analysis), MRI/MRS brain imaging, and brain activity monitoring will help researchers understand how the drug works and its impact. What are the possible benefits and risks of participating? Results from this trial will inform whether this formulation of melatonin could be used in future trials to improve outcomes for babies with HIE. By taking part in the ACUMEN study, participants will receive a potential new therapy (melatonin) to help protect their brain. The lowest dose we give has been shown to have some benefit in a small group of babies. Babies will be cared for with the highest level of neonatal care, including continuous brain wave monitoring and expert analysis of any seizures that occur. Additionally, they will be closely monitored for brain oxygen levels and blood flow, which will help improve their breathing support. This level of monitoring may not yet be the standard of care in all hospitals. Babies in the ACUMEN study may receive more detailed monitoring, which can help identify health problems earlier than in some other units. The IMP, melatonin in ethanol excipient, has demonstrated safety in preclinical studies. Potential risks and mitigations include: 1. Allergic or Immune Reactions: Preclinical data suggest these are unlikely. Participants will remain under close observation in the neonatal intensive care unit (NICU) during dosing, and medical staff will provide immediate treatment if required. 2.; Blood Alcohol Concentration (BAC): Monitoring BAC at six time intervals will mitigate risks of ethanol being above the EMA recommendations from the ethanol excipient, particularly during the initial loading dose. 3. Hypotension: monitored using invasive blood pressure measurements. Inotropic support will be available if needed. 4. Extravasation Injury: Central venous catheters will be used when possible. For peripheral cannulas, infusion sites will be monitored, and Visual Infusion Phlebitis (VIP) scores will be recorded. Study Procedures: 1. Blood Sampling: Necessary for pharmacokinetic (PK) and exploratory biomarker analysis, these will remain within EMA-recommended limits. Sampling for exploratory biomarker analysis will cease if haemoglobin levels fall below the transfusion threshold. 2. aEEG/EEG Monitoring: Procedures will be performed by highly trained staff using non-invasive gel probes to maximise comfort. 3. MRI/MRS Imaging: Non-invasive scans may cause mild discomfort due to noise. MRI-compatible incubators and standardised protocols will reduce potential stress. 4. Modified Sarnat Neurological Assessments: Conducted to evaluate the severity of hypoxic-ischaemic encephalopathy (HIE). Staff are trained using standardised pathways to minimise distress. Sample Stability and Loss: 1. Blood samples may be lost, unstable, or delayed during shipment. Mitigations include: 2. A laboratory management plan with explicit instructions on sample handling. 3. Stability testing to confirm melatonin and ethanol remain stable during transit. 4. Clear shipping protocols to maintain sample integrity. 5. Site training during initiation visits to ensure standardised sample handling. Standard of Care (SoC): The study will not replace or withhold standard care treatments. Monitoring (e.g., aEEG/EEG, NIRS) will complement existing protocols for cooling therapy and provide local teams with enhanced tools to manage critically unwell infants effectively. Where is the study run from? The Comprehensive Clinical Trials Unit at University College London (UK) When is the study starting and how long is it expected to run for? February 2025 to March 2027 Who is funding the study? Medical Research Council (MRC) (UK) Who is the main contact? cctu.acumen@ucl.ac.uk The overall aim of the study is to identify the Recommended Phase II Dose (RP2D) based on the totality of data and outcomes are listed below. The primary outcomes are: 1. Safety: the safety profile of melatonin across dose levels being studied assessed based on the occurrence of dose-limiting events (DLE): DLEs will be evaluated continuously from the time of first administration of the IMP (T0) until 96 hours post-T0 (T+96 hours). T0 is defined as the time of the first loading dose administration, which must occur within the first six hours of birth. 2. The attainment of putative therapeutic plasma melatonin levels (in the range of 15-30 mg/L) across dose levels being studied: plasma melatonin levels will be evaluated at predefined timepoints during the dosing period up to T+96 hours, with T0 as the starting point. 3. The attainment of putative ethanol safety (BAC levels <0.25 g/L across dose levels being studied: blood alcohol concentration will be monitored and evaluated at predefined intervals during the dosing period, up to T+96 hours from the initial loading dose (T0). 1. Pharmacokinetic Model (PK): 1.1. Estimation of population PK parameters of melatonin in the target population. 1.2. Estimation of population PK parameters of ethanol in the target population. PK parameters for melatonin and ethanol will be evaluated using blood samples collected at predefined intervals up to the 96-hour time point (T+96 hours, with T0 being the first dose administered within 6 hours of birth) 2. Establishing a Neonatal Neuroprotection Trial Network in anticipation of a Phase II RCT: 2.1. Successful harmonisation of 3T MRI scanners and acquisition of magnetic resonance spectroscopy (MRS) at days 4 to 10: 2.1.1. Evaluation of pattern and severity of injury using T1/T2 MRI and diffusion-weighted imaging (DWI). 2.1.2. Assessment of HIE severity through baseline lactate/N-acetylaspartate (NAA) statistics to inform the sample size calculation of the Phase II trial. 2.2. Successful (in >90% of enrolled babies) integration and standardising of amplitude-integrated electroencephalography aEEG/EEG monitoring throughout the cooling and rewarming periods at all centres, using recovery of background activity as a proxy for outcome (a more rapid recovery of background voltage is associated with a favourable outcome). aEEG/EEG monitoring will be continuous throughout cooling (0–72 hours) and rewarming (72–96 hours). 2.3. Successful (>90% of enrolled babies) integration of continuous cerebral near-infrared spectroscopy (NIRS) as part of the neurocritical care management for infants with HIE. NIRS data will be collected continuously throughout the same timeframe. 2.4. Successful collection (>90% of enrolled babies) of early surrogate measures of neurodevelopmental outcomes (Hammersmith Infant Neurological Examination (HINE) at 3 months, Hammersmith Neonatal Neurological Examinations (HNNE) at hospital discharge, General Movement Assessment (GMA) at 3 months and ASQ-3). 3. Recruitment: 3.1. Metrics on the acceptability of the study among potential participants’ parent/legal guardian(s) 3.2. Rates of informed consent obtained within the 6-hour timeframe 3.3. Timelines and initiation of the first dose administration within the specified 6-hour window Recruitment and consent metrics will be assessed throughout the recruitment phase (from start to completion of participant enrolment) Ethics approval required London - Central Research Ethics Committee

3rd Floor 3 Piccadilly Place London Road

Manchester United Kingdom M1 3BN 25/LO/0170 10.1186/ISRCTN61218504 1011409 CPMS: 68402, CTU/2020/348 1011409 68402 CTU/2020/348 Open-label non-randomized study Interventional Non randomised study Safety 2027-03-31T00:00:00.000Z United Kingdom England Scotland Australia Ireland Uclh

250 Euston Road

London England NW1 2PQ NV132@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal London Hospital

The Royal London Hospital Alexandra House

London England E1 1BB St Mary's Hospital

Oxford Road

Manchester England M13 9WL R0A05@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Infirmary of Edinburgh at Little France

51 Little France Crescent Old Dalkeith Road Edinburgh

Lothian Scotland EH16 4SA S314H@2.16.840.1.113883.2.1.3.8.2.16.2 Liverpool Womens Hospital

Crown Street

Liverpool England L8 7SS RTV0E@2.16.840.1.113883.2.1.3.2.4.18.48 Cork Maternity Hospital

Wilton Road Wilton

Cork Ireland T12 YE02 Coombe Hospital

Cork St Saint James

Dublin Ireland D08 XW7X Rotunda Hospital

Parnell Square E Rotunda

Dublin Ireland D01 P5W9 Flinders Medical Centre

Flinders Dr

Bedford Park Australia SA 5042 Monash Children’s Hospital

246 Clayton Rd

Clayton Australia VIC 3168 Patient 1. Baby admitted to the Neonatal Intensive Care Unit (NICU) with moderate-severe hypoxic-ischaemic encephalopathy (HIE) meeting eligibility criteria for therapeutic hypothermia (HT) (in accordance with local guidelines) and: 1.1. Born at ≥36 completed weeks gestation 1.2. Clinically stable* at the time of IMP administration 1.3. Invasive blood pressure monitoring in situ prior the administration of the IMP loading dose 2. All participants will undergo a further assessment of HIE grade as determined by amplitude-integrated EEG (aEEG)/EEG and/or a Modified Sarnat neurological examination prior to IMP administration 2.1. Sentinel Participant Criteria Only: must not meet the criteria for severe HIE 3. Informed consent from parents/guardians/person with legal responsibility *Definition of Clinical Stability: Eligibility of the participant must be rechecked prior to administration of the IMP given the varying clinical status of these infants. Stability will take the following into consideration: 1. Well placed central venous catheter or patent peripheral cannula in situ 2. Mean blood pressure (with or without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) within 30 mins prior to IMP administration 3. Clinical or electrical seizures, if present, controlled with anti-seizure medications 4. Clinical observations within acceptable range for an infant undergoing therapeutic hypothermia 5. No clinical stability concerns from the attending neonatologist Updated 14/07/2026: * Definition of Clinical Stability Eligibility of the participant must be rechecked prior to administration of the IMP given the varying clinical status of these infants. Stability will take the following into consideration: 1. Well placed central venous catheter or patent peripheral cannula in situ. 2. Haemodynamic stability within 30 minutes prior to IMP administration: 2.1. Mean blood pressure (without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of the loading dose. 2.2. Mean blood pressure (with or without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of each maintenance dose. 2.2.1. The participant must not be receiving more than one vasoactive inotrope. 2.2.2. The Vasoactive-Inotropic Score (VIS) must be ≤10. The VIS score is calculated as VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + [100 x adrenaline (µg/kg/min)] + [100 x noradrenaline (µg/kg/min)] 3. No evidence of acute kidney injury resulting in hyperkalaemia (defined as a serum potassium >6.5 mmol/L) that continues to rise despite stopping potassium-containing infusions and potassium-sparing drugs (based on the most recent available blood test result). 4. No clinical concerns of acute liver failure for the loading dose†. 5. No evidence of ongoing acute liver failure defined as INR>3 (despite administration of parenteral vitamin K or clotting factor replacement) for administration of maintenance doses based on the most recent blood test. 6. Clinical or electrographic seizures, if present, controlled with anti-seizure medications. If there are seizures, these must not be ongoing or uncontrolled despite anti-seizure medications. 7. Clinical observations within acceptable range for an infant undergoing therapeutic hypothermia. 8. No clinical stability concerns from the attending neonatologist. † Routine coagulation (INR) monitoring beyond baseline is not mandated for the trial and should be performed at the discretion of the clinical team in line with local standard practice. Coagulation screen results are unlikely to be available pre-IMP loading dose administration. Neonate All 60 0 1. Baby would be >6 hours of age when IMP administered 2. Initiation of IMP unlikely to be administered within 6 hours of birth 3. Infants born in very poor condition or judged too sick to be included (high risk of mortality) in an experimental first-in-human study, for example, infants that are requiring maximal intensive care therapy or in a condition considered to be life-limiting. 4. Postnatal hypoxic insult without any evidence of HIE at birth. 5. Birth weight less than 2nd centile for gestation on UK-WHO growth charts# 6. Congenital anomalies, i.e., any major antenatal diagnosed congenital abnormalities such as congenital heart disease, suspected or known chromosomal abnormalities 7. Infant is participating or intends to participate in another interventional study during the birth hospitalisation (note: does not include observational studies) 8. Parents/legal guardians unable to give consent due to learning or other difficulties Please note that in the event of multiple births: 1. If one baby has HIE, participation in the trial will be offered 2. If both/multiple babies have HIE, participation in the trial will not be offered # - https://www.rcpch.ac.uk/sites/default/files/Boys_neonatal_and_infant_close_monitoring_growth_chart.pdf https://www.rcpch.ac.uk/sites/default/files/Girls_neonatal_and_infant_close_monitoring_growth_chart.pdf Removed 14/07/2026: 7. Head circumference less than 2nd centile adjusted to sex of the baby on UK-WHO growth charts# 2025-10-29T00:00:00.000Z 2026-11-30T00:00:00.000Z Moderate to severe hypoxic-ischaemic encephalopathy (HIE) in newborn infants Neonatal Diseases The intervention is a novel formulation of melatonin in ethanol 50 mg/ml solution for infusion administered to newborn babies with moderate-severe HIE to augment therapeutic hypothermia (HT). HT will be started in eligible babies according to local guidelines as soon as possible after birth. Administration of IMP will be provided over 6 infusions: A loading dose administered over 2 hours within 6 hours of birth 5 x maintenance doses every 12h from 24h after initiation of loading dose (administered over 2 hours) ACUMEN is an open-label, non-randomized study, meaning all enrolled participants receive IMP in addition to standard therapeutic hypothermia. The dose levels to be considered as part of this trial are outlined in the table below. Dose Level 1 and Dose Level 2 will be investigated as fixed starting points of the dose-escalation phase. From Dose Level 3 onwards, dose levels may be skipped based on accumulating safety data and population pharmacokinetic (POP-PK) modelling. In total, it is anticipated that 4 dose levels will be explored during the dose-escalation part of the study. Loading doses: Dose Level 1: 5 mg/kg Dose Level 2: 10 mg/kg Dose Level 3: 15 mg/kg Dose Level 4: 20 mg/kg Dose Level 5: 25 mg/kg Dose Level 6: 30 mg/kg Dose Level 7: 35 mg/kg Dose Level 8: 40 mg/kg The ACUMEN study consists of two phases: Dose Escalation Phase: Multiple cohorts of neonates will receive different dose levels of IMP. There are eight predefined dose levels, but only four will be investigated based on accumulating safety data and pharmacokinetic (PK) modelling. Cohort Expansion Phase: Once an optimal dose level is identified, a larger cohort will receive this dose to determine the recommended Phase II dose (RP2D). Participants will be followed up for 3 months as part of the ACUMEN trial. Drug Phase I Melatonin Data sharing statement to be made available at a later date 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40846329/ (added 27/08/2025) Protocol

0d769737-d299-4a1d-9cf8-a051474fe132 a30badcd-faa1-401c-a772-dbebfe5d6b97 a571a051-aab7-4bed-875e-2fe70fd8d88a c7cbb333-1170-4ef8-bcaf-bea400de586a No Felicia Ikeji Scientific

90 High Holborn, 2nd Floor

London United Kingdom WC1V 6LJ +44 (0)20 3108 4255 cctu.acumen@ucl.ac.uk Public Nikki Robertson Scientific Principal investigator

74 Huntley Street

London United Kingdom WC1E 6HX +44 (0)2076796052 n.robertson@ucl.ac.uk Public The Comprehensive Clinical Trials Unit at University College London University/education Non-commercial Medical Research Council Developmental Pathway Funding Scheme (UKRI MRC DPFS) 17799294 true Edmond J Safra, Accelerating Clinical Trials in Parkinson’s Disease (EJS ACT-PD) - a multi-arm multi-stage platform trial for potential disease-modifying approaches EJS ACT-PD The primary objective of the EJS ACT-PD Trial is to determine whether the active trial treatments result in a ≥30% reduction in the rate of disease progression between the active treatment and placebo arms as measured by the MDS-UPDRS Parts I and II combined. Secondary objectives: 1. The safety and tolerability of the active treatments for people with PD when taken for up to 3 years 2. The effects of the treatments on quality of life and patient-reported efficacy outcomes in people with PD 3. The effects of the treatments on objective assessments of the motor severity of PD 4. The effects of the treatments on cognitive function in people with PD 5. The effects of the treatments on the quality of life of partners of people with PD 6. The cost-effectiveness of the treatments for people with PD compared to the current standard of care 7. The success of our recruitment and retention strategies on recruiting a participant sample that is representative of the population of people with Parkinson’s in the UK via various evaluation options (to be further defined via a future EDI sub-study) Background and study aims Parkinson's disease (PD) is currently the fastest-growing neurological condition globally. It is projected to affect 172,000 people in the UK by 2030, with the current annual cost to the country being about £3.6 billion. The disease progressively impairs physical abilities, leading to increased disability, falls, and difficulties with speech, swallowing, mood, thinking, and memory. While existing treatments can alleviate some symptoms, their effectiveness diminishes over time, and they can cause severe side effects. This trial uses a Multi-Arm, Multi-Stage (MAMS) design where multiple treatments are tested simultaneously in separate groups, called "arms". Each treatment is compared against a placebo, a dummy treatment with no active ingredients, to evaluate its effectiveness and safety. Who can participate? Patients with Parkinson’s disease What does the study involve? Throughout the trial, each treatment undergoes periodic reviews, known as interim analyses, to assess its safety and potential benefits. If a treatment shows promise, it continues in the trial until a final assessment determines its overall effectiveness. Treatments that do not show positive results are discontinued and replaced with new candidates. This approach reduces the number of participants needed to obtain reliable results and is more cost-effective and faster than conducting separate trials for each treatment. The treatments selected for this trial were chosen based on careful consideration of existing evidence regarding their safety and effectiveness. The initial treatments include telmisartan and terazosin. Participants will be followed up for up to 36 months. After an in-person screening visit, all remaining visits at 3 months, 6 months and then every 6 months after, for a total of up to 36 months can be completed remotely. The visits will include questionnaires, assessment of Parkinson’s symptoms and discussions about any side effects. Participants will informed of trial progress. Results will be shared via the trial website and published in a medical journal. Following the screening and baseline appointments, participants will be contacted twice yearly for follow-up visits with additional telephone calls during the titration period, at 3 months and 9 months during their first year of participant compared to once per year or less in standard of care. To minimise the burden to participants, only the screening visit is mandated as an in-person visit. The remaining follow-up visits can be conducted fully remotely, either by video call or telephone. However, the visits can be conducted in-person, if the participant wishes. Where a participant attends clinic, travel expenses will be reimbursed of up to £40 per visit. Prior to entering the study, the participant will be asked to have a blood test and ECG for safety tests. An additional blood sample for translational work will also be requested at the screening and final study visits. The partner sub-study involves the participant’s partner completing quality of life questionnaires regarding their informal care responsibilities. To minimise the risk of the participant not being comfortable with their partner's involvement, the partner can only be recruited if the participant consents to this. The participant and partner information sheets will be available to the participant and they will be encouraged to discuss them both with their partner. The participant will be able to withdraw their consent for their partner’s participation in the sub-study at any point during the study. What are the possible benefits and risks of participating? The trial treatments, telmisartan and terazosin, are repurposed drugs and therefore have a well-known safety profile. The most common side effect expected is orthostatic hypotension. To assist with monitoring this, participants will be supplied with a blood pressure monitor and clear instructions as to how to use at the screening visit, for use at their home. If the participant experiences symptoms of low blood pressure, such as feeling faint or dizzy, they can check their blood pressure and contact the site study team for further clinical management. If any low blood pressure symptoms are reported to site staff during a remote trial visit, the site staff can request that the participant takes their blood pressure at home to inform whether this needs clinical follow-up. As the effects of the trial treatment are unknown on pregnancy and fertility, participants or their partners (if a woman of childbearing potential) must agree to use contraception throughout the trial treatment period and for 70 days after the final dose of trial treatment. Participants will be reminded at follow-up visits of the importance of using appropriate contraception. Additionally, for WOCP participants, before entering the study, a urine pregnancy test will be required and will be repeated before starting IMP if this occurs more than 14 days after. The above information has been included in the patient information sheets and will be discussed prior to enrolment. Training will be provided to sites to highlight the risks and the mitigation strategies. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? December 2024 to July 2031 Who is funding the study? National Institute for Health and Care Research (UK) Who is the main contact? EJS ACT-PD Trial Team at MRC CTU, mrcctu.ejsactpd@ucl.ac.uk The rate of Parkinson’s disease progression between the active treatment and placebo arms is measured by the MDS-UPDRS Parts I and II combined with equal weighting at baseline, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination and week 165 Clinician reported measures: 1. Parkinson’s disease stage is measured using the Hoehn and Yahr Scale (H&Y) at screening, week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination and week 165. 2. Cognitive impairment is measured using the Montreal Cognitive Assessment (MoCA) at screening, week 0, week 26, week 52, week 104, week 156 or early termination. 3. Parkinson’s disease medication use is measured by levodopa-equivalent daily dose (LEDD) at all study visits. 4. Part III of the MDS-UPDRS in the ON medication state (remote elements only) at screening, week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination and week 165. 5. Part IV of the MDS-UPDRS in the ON medication state at screening, week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination and week 165. 6. The severity of depression is assessed by the Patient Health Questionnaire (PHQ-9) at screening, week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 7. Quality of life is assessed by the Parkinson’s Disease Questionnaire (PDQ-8) at week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 8. Carers' quality-of-life is assessed by the questionnaire for parkinsonism (PQoL Carers) at week 0, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 9. Ability to enjoy life is assessed by the ICEpop CAPability measure for Older people (ICECAP-O) at week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 10. Health-related quality of life is assessed by the EuroQol five-dimension scale questionnaire (EQ-5D-5L) at week 0, week 13, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 11. Use of health and social care resources is assessed by the resource use questionnaire (which includes modified Client Service Receipt Inventory [CSRI] and modified iMTA Valuation of Informal Care Questionnaire [iVICQ]) at week 0, week 26, week 52, week 78, week 104, week 130 and week 156. 12. Carer health-related quality of life is assessed by the EuroQol five-dimension scale questionnaire (EQ-5D-5L) at week 0, week 26, week 52, week 78, week 104, week 130, week 156 (end of study visit) or early termination. 13. Suicidal ideation is assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, week 156 (end of study visit) or early termination. 14. Other safety and tolerability measures are assessed through the collection of adverse events/serious adverse events, treatment compliance and trial withdrawal and treatment discontinuation rates at all study visits. 15. Participant experience before, during and after trial participation is assessed by an amended Study Participant Feedback Questionnaire (SPFQ) at week 0, week 78, week 156 (end of study visit) or early termination. 16. Participant feedback collected at the end of trial participation via exit interview with an individual external to their study site. Ethics approval required -

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- United Kingdom - 25/LO/0039 10.1186/ISRCTN17799294 1009921 CPMS: 56062, ND002 1009921 56062 ND002 Randomized controlled-placebo double-blind parallel-group multi-arm multi-stage (MAMS) trial Interventional Randomised controlled trial Safety Efficacy 2031-07-31T00:00:00.000Z United Kingdom England Wales Clinical Ageing Research Unit

Campus for Ageing and Vitality

Newcastle upon Tyne United Kingdom NE4 5PL Royal Hallamshire Hospital

Glossop Road

Sheffield United Kingdom S10 2JF 5EQHH@2.16.840.1.113883.2.1.3.2.4.18.48 Salford Royal Hospital

Stott Lane Eccles

Salford United Kingdom M6 8HD 01GAW@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital

Mindelsohn Way Edgbaston

Birmingham United Kingdom B15 2GW John Van Geest Centre for Brain Repair site

Robinson Way

Cambridge United Kingdom CB2 0PY University College London Hospital

250 Euston Road

London United Kingdom NW1 2PG Royal London Hospital

Whitechapel Rd

London United Kingdom E1 1FR St Georges Hospital

Blackshaw Rd

London United Kingdom SW17 0QT John Radcliffe Hospital

Headley Way Headington

Oxford United Kingdom OX3 9DU Royal Sussex County Hospital

Eastern Rd, Brighton and Hove

Brighton United Kingdom BN2 5BE Royal United Hospital

Combe Park

Bath United Kingdom BA1 3NG RNZ71@2.16.840.1.113883.2.1.3.2.4.18.48 Derriford Hospital

Derriford Road Crownhill

Plymouth United Kingdom PL6 8DH RK950@2.16.840.1.113883.2.1.3.2.4.18.48 Ninewells Hospital

Ninewells Avenue

Dundee United Kingdom DD1 9SY T101H@2.16.840.1.113883.2.1.3.8.2.16.2 University Hospital of Wales

Heath Park

Cardiff United Kingdom CF14 4XW RWMBV@2.16.840.1.113883.2.1.3.2.4.18.48 Belfast City Hospital

51 Lisburn Rd

Belfast United Kingdom BT9 7AB ZT00104@2.16.840.1.113883.2.1.3.10.2 The Walton Centre

Lower Ln Fazakerley

Liverpool United Kingdom L9 7LJ Charing Cross Hospital

Fulham Palace Road

London United Kingdom W6 8RF RDU92@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Southampton

Tremona Road

Southampton United Kingdom SO16 6YD Royal Infirmary of Edinburgh at Little France

51 Little France Crescent Old Dalkeith Road Edinburgh

Lothian United Kingdom EH16 4SA S314H@2.16.840.1.113883.2.1.3.8.2.16.2 King's College Hospital

Denmark Hill

London United Kingdom SE5 9RS 5LD98@2.16.840.1.113883.2.1.3.2.4.18.48 Lewisham Hospital

Lewisham High Street

London United Kingdom SE13 6LH RAV04@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth University Hospital

1345 Govan Road

Glasgow United Kingdom G51 4TF G405H@2.16.840.1.113883.2.1.3.8.2.16.2 Queens Hospital

Rom Valley Way

Romford United Kingdom RM7 0AG V43559@2.16.840.1.113883.2.1.3.2.4.18.48 Leeds General Infimary

Great George Street

Leeds United Kingdom LS1 3EX D6A2L@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Devon & Exeter Hospital (wonford)

Barrack Road

Exeter United Kingdom EX2 5DW RH801@2.16.840.1.113883.2.1.3.2.4.18.48 North Tyneside General Hospital

Rake Lane

North Shields United Kingdom NE29 8NH RTDAL@2.16.840.1.113883.2.1.3.2.4.18.48 Christchurch Hospital

Fairmile Road

Christchurch United Kingdom BH23 2JX RNZ15@2.16.840.1.113883.2.1.3.2.4.18.48 Poole Hospital

Longfleet Road

Poole United Kingdom BH15 2JB 5QN33@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital

Sheriff Hill

Gateshead United Kingdom NE9 6SX RR7EN@2.16.840.1.113883.2.1.3.2.4.18.48 Ipswich Hospital

Heath Road

Ipswich United Kingdom IP4 5PD RWN59@2.16.840.1.113883.2.1.3.2.4.18.48 Wrexham Maelor Hospital

Croesnewydd Road Wrexham Technology Park

Wrexham United Kingdom LL13 7TD 7A1A4@2.16.840.1.113883.2.1.3.2.4.18.48 North West Wales NHS Trust

Ysbyty Gwynedd Penrhosgarnedd

Bangor United Kingdom LL57 2PW RT7@2.16.840.1.113883.2.1.3.2.4.18.48 Scarborough Hospital

Woodlands Drive

Scarborough United Kingdom YO12 6QL RR854@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Shrewsbury Hospital

Mytton Oak Road

Shrewsbury United Kingdom SY3 8XQ RXWAS@2.16.840.1.113883.2.1.3.2.4.18.48 St Peters Hospital

Guildford Road

Chertsey United Kingdom KT16 0PZ RVRA3@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Coventry and Warwickshire NHS Trust

Walsgrave General Hospital Clifford Bridge Road

Coventry United Kingdom CV2 2DX RKB@2.16.840.1.113883.2.1.3.2.4.18.48 William Harvey Hospital

Kennington Road Willesborough

Ashford United Kingdom TN24 0LZ RWF37@2.16.840.1.113883.2.1.3.2.4.18.48 Yeovil District Hospital

Higher Kingston

Yeovil United Kingdom BA21 4AT Musgrove Park Hospital

Musgrove Park Hospital

Taunton United Kingdom TA1 5DA NT489@2.16.840.1.113883.2.1.3.2.4.18.48 Norfolk & Norwich University Hospital

Colney Lane Colney

Norwich United Kingdom NR4 7UY RM102@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Diagnosis by neurologist, movement disorders specialist or appropriately experienced clinician of clinically established or clinically probable PD in the clinician’s opinion. In the presence of any diagnostic doubt, the Movement Disorder Society diagnostic criteria will be applied. 2. Diagnosed with Parkinson’s disease at age 30 years or older, no upper age limit. 3. Currently on Parkinson’s medication (levodopa-containing preparations or dopamine agonists, used either as single agents or in combination) for at least 2 months prior to the screening visit. 4. Female participants who are women of child-bearing potential (WOCP) must have confirmation of a negative pregnancy test at the screening visit. See Protocol Table 1 and Section 6.6.4 for details on pregnancy testing. 5. Female participants who are WOCP and male participants with partners who are WOCP must be taking appropriate contraceptive treatment(s). See Protocol Section 6.6.4 for details on pregnancy and Appendix 1 for details on acceptable contraception. 6. Documented informed consent. 7. Eligible for at least one of the active treatment arms (see treatment-specific exclusions). 8. Randomisation should ideally take place within 3 weeks of the screening visit but no later than 4 weeks after the screening visit. 9. If a participant is being re-randomised into the trial, additional timing of entry requirements must also be met: 9.1. For participants re-randomised after completing 36 months’ follow-up and the arm was not closed due to lack of activity, a 26-week washout period from the last dose of IMP must be completed before their screening visit. If the primary analysis indicates that the IMP was ineffective then this washout period can be reduced to 6 weeks. 9.2. For participants being re-randomised following treatment arm termination due to lack of activity, a 6-week washout period from their last dose of IMP must be completed prior to screening assessment. Adult 30 Years All 1200 1. Diagnosis or suspicion of other cause for parkinsonism such as atypical parkinsonism, dystonic tremor, essential tremor, or drug-induced parkinsonism. 2. Known carriers of recessive PD gene mutations PRKN, PINK1 or DJ1 (based on previous medical tests/notes). 3. Clinical diagnosis of dementia or MoCA <21 at screening visit. 4. Currently in another ongoing interventional trial or exposure to any IMP within an experimental interventional trial within 6 months prior to screening visit (exception for EJS ACT-PD participants that are being re-randomised due to treatment arm termination following lack of activity as only a 6-week washout period is required.) 5. Unable or unwilling to comply with study requirements. 6. Diagnosis of clinically significant depression or >14 on PHQ-9 at screening visit. 7. Current suicidal ideation within one year prior to the screening visit as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS). 8. Previous brain surgery or on a waiting list for brain surgery including deep brain stimulation and/or currently taking or on a waiting list for advanced therapies for Parkinson’s disease (such as any infusion therapy). 9. Monotherapy with monoamine oxidase-B inhibitor (MAO-BI). 10. Previous exposure to any of the currently recruiting IMPs within 6 months prior to the screening visit or previous intolerance of any of the IMPs. 11. Participant has any concurrent medical condition, abnormal laboratory tests, progressive neurological disorder or uncontrolled, clinically significant systemic disease that, in the opinion of the Investigator, could cause study participation to be detrimental to the participant (e.g., end-stage renal failure, severe heart failure, unstable angina, uncontrolled hypertension or uncontrolled orthostatic hypotension, severe liver disease, uncontrolled diabetes, or severe anaemia). 12. Pregnant or breastfeeding or intending to become pregnant during the study or within 70 days after the final dose of the study drug. 13. Confirmed diagnosis of cancer and is requiring active management of that cancer and/or in the view of the local team, the diagnosis and/ or its treatment may compromise their ability to remain participating in the trial for 36 months or tolerate any of the active treatments. 14. Participants with hepatobiliary disorders or abnormal liver function tests (ALT or AST >2x the upper limit of normal) at the screening visit. 15. Participants with a history of alcohol/drug abuse/dependence within the 3 years prior to the screening visit. 16. Participants with either of the following: 16.1. Sitting systolic blood pressure (SBP) less than 100 mmHg or sitting diastolic blood pressure (DBP) less than 50 mmHg, irrespective of symptoms 16.2.1. Orthostatic hypotension defined as any of the following: 16.2.2. Decrease in BP >20 mmHg systolic or >10 mmHg diastolic on supine to standing, associated with clinical symptoms 16.2.3. Decrease in BP >30 mmHg systolic and/or BP >15 mmHg diastolic on supine to standing regardless of symptoms 16.2.4. If the lowest BP on standing is less than 100 mmHg or lowest diastolic on standing is less than 50 mmHg If, in the assessing clinician’s opinion, the postural BP drop is attributable to transient/reversible factors (e.g. related to the use of antihypertensives, dehydration, elevated room temperature, postprandial state), one repeated orthostatic BP assessment is allowed once those factors are addressed; additional re-screening will be allowed if the participant has their hypotension/orthostatic hypotension treated. TREATMENT SPECIFIC EXCLUSION CRITERIA TELMISARTAN 1. Participants currently taking sartans (AT1 angiotensin receptor antagonists), aliskiren, ACE inhibitors or potassium-sparing diuretics. 2. Participants with a known hypersensitivity or intolerance to sartans (AT1RAs) 3. Participants with a history of angioedema. 4. Participants with known aortic or mitral stenosis that the investigator judges to make telmisartan use potentially unsafe. 5. Participants with known renal artery stenosis. 6. Participants with hyperkalaemia (serum potassium (K+) level of ≥ 5.5 mmol/l). If hyperkalaemia is identified, one re-screening will be allowed, either within 4 weeks or after the identification and treatment of precipitants. 7. Participants currently taking lithium or taken within the previous 6 months. TERAZOSIN 1. Participants currently using alpha blockers other than tamsulosin (alfuzosin, silodosin, prazosin, terazosin, and doxazosin), including natural supplements with this action (e.g. yohimbine). 2. Participants with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. 3. Participants with a known sensitivity to quinazolines e.g. alfuzosin, silodosin, prazosin, terazosin, doxazosin, erlotinib, gefitinib, afatinib, lapatinib, and vandetanib. 2025-09-01T00:00:00.000Z 2029-06-30T00:00:00.000Z Parkinson’s disease (PD) Nervous System Diseases The EJS ACT-PD trial has three treatment arms: placebo, telmisartan and terazosin. All treatment arms are in addition to Standard of Care. As EJS ACT-PD is a blinded trial, all participants will receive the same dosing regime and assessment schedule. Following randomisation, participants will complete a 5-week titration phase which involves taking one capsule a day. During the titration phase (weeks 1 to 5) participants will be dispensed one bottle per week during the titration phase labelled 1, 2, 3 etc to correspond with the week. The bottles will contain the following IMP doses: Placebo – Week 1-5: one capsule per day Telmisartan – Week 1-3: one 20 mg capsule per day; Week 4-5: one 40 mg capsule per day Terazosin – Week 1: one 1 mg capsule per day; Week 2: one 2 mg capsule per day; Week 3: one 3 mg capsule per day; Week 4: one 4 mg capsule per day; Week 5: one 5 mg capsule per day If the participant tolerates the IMP dose during the titration phase, they will continue onto the treatment phase, if they are happy to do so. The treatment phase also involves taking one capsule per day for up to 36 months at the following doses: Placebo – one capsule per day Telmisartan – one 40 mg capsule per day Terazosin – one 5 mg capsule per day The screening visit will be conducted in person with all remaining visits being completed remotely, if the participant wishes. Following the remote baseline appointment, participants will be contacted twice yearly for follow-up visits with additional telephone calls during the titration phase, at 3 months and 9 months during the first year of participation. The study visits will include questionnaires, an assessment of Parkinson’s symptoms and a discussion of any side effects. The EJS ACT-PD Trial will use randomised double-blind, placebo-controlled comparisons. Participants will be randomly assigned equally to each of the actively recruiting treatment arms for which they are eligible. Randomisation will use minimisation. For participants eligible for both active treatment arms, the ratio between the three arms will be 1:1:1. If participants are ineligible for a specific active treatment arm, they can be assessed for eligibility and randomised to other arms for which they are eligible. For participants eligible for only one active treatment arm, the ratio between that arm and the placebo arm will be 1:1. Participants will be randomised at each site via the EJS ACT-PD eDC System, a centrally managed system hosted by MRC CTU, accessible to authorised members of the research teams at recruiting site using a web-based interface. Eligibility and consent will be verified before each participant is randomised and is then confirmed within the system at the time of randomisation. Drug Phase III Telmisartan, terazosin Research teams may approach the MRC CTU with a formal data-sharing request detailing the specific requirement, proposed research, qualification of researchers and publication plan if they are interested in using EJS ACT-PD data. The request will be reviewed by the trial committees. Data and/or samples will be available for sharing following the end of a trial arm and the unblinding of participants. Researchers wishing to access the EJS ACT-PD Trial data should contact the Trial Management Group in the first instance. Following trial completion, requests for data and/ or sample sharing will be reviewed by an EJS ACT-PD access committee which will include the trial’s Chief Investigators. Data and/ or samples will be shared during the trial according to the CTU’s controlled access approach, based on the following principles: 1. No data and/or samples should be released that would compromise an ongoing trial or study. 2. There must be a strong scientific or other legitimate rationale for the data and /or samples to be used for the requested purpose. 3. Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data and /or samples before key trial data are made available to other researchers. 4. The resources required to process requests should not be underestimated, particularly successful requests which lead to preparing data for release. Therefore, adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources. 5. Data and/ or sample exchange complies with Information Governance and Data Security Policies in all of the relevant countries. 6. Data and/ or sample exchange is only provided following the execution of a valid material transfer agreement (MTA). Anonymised study data will be made available on appropriate data-sharing platforms. Available on request

Study website Migrated from study website field

0f23bcb9-b43b-4bf8-85fe-0efe0166949e 88feb389-7af8-4735-8112-81d48a2f6321 0b619218-0bd9-42a7-874d-ca87da442278 5255e23d-4e3f-4f9b-8895-6144fa0b74c0 aeeca261-0f97-452a-8090-b1c7c6be885e Yes EJS ACT-PD Trial Team at MRC CTU Public Scientific

MRC CTU at UCL ICTM 2nd Floor 90 High Holborn

London United Kingdom WC1V 6LJ - mrcctu.ejsactpd@ucl.ac.uk Public Thomas Foltynie Principal investigator

250 Euston Road

London United Kingdom NW1 2PG +44 (0)203 4488726 t.foltynie@ucl.ac.uk Public Camille Carroll Principal investigator

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Clinical Ageing Research Unit Campus for Ageing and Vitality

Newcastle upon Tyne United Kingdom NE4 5PL - camille.carroll@newcastle.ac.uk Public University College London University/education https://ror.org/02jx3x895 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 25803759 true Single Unit Neurophysiological Architecture of the Neocortex (SUNAN): a single centre, unblinded, basic interventional science study using a Neuropixels probe to record and describe neuronal activity in humans undergoing a planned neurosurgical procedure on the brain SUNAN SUNAN is a single-centre, unblinded, basic interventional science study using a Neuropixels probe to record and describe individual neuronal activity in human participants who are undergoing a planned neurosurgical procedure on the brain. Background and study aims The Single Unit Neurophysiological Architecture of the Neocortex (SUNAN) study aims to describe single-unit neurophysiological activity recorded in the human brain during planned neurosurgery. By leveraging Neuropixels probes, the study seeks to provide insights into brain function and the neurophysiological impact of various neurological conditions. The primary objective is to report the number and characteristics of well-isolated neuronal units recorded intraoperatively, contributing to a deeper understanding of human neurophysiology. Who can participate? Patients aged 18 years and over undergoing a transcranial neurosurgical procedure at the National Hospital for Neurology and Neurosurgery (NHNN) in which part of the cerebral cortex will be resected or transgressed as part of the surgical approach to reach a deeper target or by the passage of a surgical implant, or surgery felt to be technically suitable for the neurophysiological recording technique What does the study involve? The study involves intraoperative neurophysiological recording using Neuropixels probes during planned brain surgeries. The procedure adds up to a total of 30 minutes to standard surgical time, including a maximum of 15 minutes of recording. In awake surgeries, participants may perform neurological tasks. Sub-studies involving cerebrospinal fluid (CSF) and tissue biopsies are optional components. What are the possible benefits and risks of participating? There are no direct clinical benefits to participants. The primary benefit is contributing to neuroscientific knowledge, potentially benefiting future patients. Participants receive a thank-you card with a printout of their neuronal recordings. The main risks relate to: 1. Neuropixels probe fracture 2. Injury as a result of Neuropixels probe insertion 3. Infection as a result of probe insertion or surgical sterility compromised 4. Planned surgery time extended Where is the study run from? The study is run from the NHNN at Queen Square, London (University College London NHS Foundation Trust) and sponsored by University College London and the Comprehensive Clinical Trials Unit (CCTU). When is the study starting and how long is it expected to run for? January 2024 to January 2029 Who is funding the study? The Francis Crick Institute 8. Who is the main contact? 1. Mr William Muirhead (Chief Investigator), Consultant Neurosurgeon, The NHNN, william.muirhead@crick.ac.uk 2. The SUNAN Trial Team, cctu.sunan@ucl.ac.uk. Descriptive reporting on the number of well-isolated single neuronal units observed during the neurophysiological recording of the brain during planned neurosurgery. The neurophysiological activity of the brain will be described through an analysis of the electrical activity recorded. The detection of spikes represents the depolarisation of single neuronal units (“single units”). Well-isolated single-units will be defined by clustering metrics, interval spike interval violations and/or other neurophysiological analysis. Descriptive reporting will include the number of individual units recorded, their spiking rates and correlation. Timepoint – At time of planned neurosurgery. Secondary outcome measures will be reported for each participant to gather information on the recording technique. For example, a description of the recording setting may include the arrangement of ground and reference electrodes as well as the operative setup. At a minimum of 6-month intervals throughout the study, the secondary outcomes will be reviewed and discussed by the research team. The following secondary outcome measures will be assessed through study completion, an average of 1 year: 1. Reporting on the experience of using large-scale single-unit recording techniques in humans undergoing neurosurgery 2. Reporting on iterations made to the surgical and electrophysiological technique 3. Reporting on potential refinements that could be made to the described technique which could enable better quality data and that could be of benefit to other researchers conducting similar work. For example, equipment set-up/noise restrictions in the theatre Ethics approval required North East - Newcastle and North Tyneside 1 Research Ethics Committee (Health Research Authority)

2nd Floor, 2 Redman Place

London United Kingdom E201JQ 24/NE/0226 10.1186/ISRCTN25803759 314485 CCTU TAG: CTU/2022/422, Sponsor R&D: 159671, Funder grant: CR2023/031/20612 314485 CCTU TAG: CTU/2022/422, Sponsor R&D: 159671, Funder grant: CR2023/031/20612 Single-centre unblinded basic interventional science study Interventional Basic science study involving human participants Other 2029-01-01T00:00:00.000Z United Kingdom England National Hospital for Neurology & Neurosurgery

Queen Square

London United Kingdom WC1N 3BG RRVN0@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Aged 18 years and over 2. Able to give their own consent and written informed consent to participate 3. Undergoing a transcranial neurosurgical procedure at the National Hospital for Neurology and Neurosurgery in which part of the cerebral cortex will be: 3.1. Resected e.g., as removal of part of a tumour or epilepsy focused Or 3.2. Transgressed as part of the surgical approach to reach a deeper target e.g., resection of a deep tumour or cavernoma Or 3.3. Transgressed by the passage of a surgical implant e.g., a ventriculoperitoneal shunt catheter or deep brain stimulation electrode 4. Surgery felt to be technically suitable for the neurophysiological recording technique by the Chief Investigator and responsible Consultant Neurosurgeon. For example, participants having surgery in an unusual position may present problems for the neurophysiological recording step. Mixed 18 Years All 50 1. Participants who lack the capacity to give informed consent. 2. Participants who are pregnant or breastfeeding at the time of surgery. 3. Participants deemed to be unsuitable for recruitment to the study by the responsible Consultant Neurosurgeon. If in the view of the treating consultant involvement in the study would compromise the patient’s surgery or present an unacceptable risk to them, they will not be recruited to the study. For example, if the participant does not meet the standard of care preoperative checks. 4. Concern from the Consultant Neurosurgeon or treating Anaesthetist that there would be an unreasonable burden on the patient to participate in the study. For example, risk due to increased length of anaesthetic time. 5. For participants requiring anaesthesia for their pre-planned brain surgery, an American Society of Anaesthesiologists (ASA) physical status classification system score of 4 and higher. 6. Participants unable to understand English sufficiently well to read the patient-facing documents and consent in English. 7. Participants not undergoing their treatment through NHS care (i.e. private patients are excluded). 2025-06-01T00:00:00.000Z 2028-02-01T00:00:00.000Z Patients undergoing planned cranial neurosurgery Surgery The SUNAN study is a basic science study involving a procedure to record single-unit neurophysiological activity with human participants who are already undergoing a transcranial neurosurgical procedure on the brain at The National Hospital for Neurology and Neurosurgery. As part of the surgery, a region of cerebral cortex on the convexity of the brain will be: 1. Resected e.g., as removal of part of a tumour or epilepsy focused Or 2. Transgressed as part of the surgical approach to reach a deeper target e.g., resection of a deep tumour or cavernoma Or 3. Transgressed by the passage of a surgical implant e.g., a ventriculoperitoneal shunt catheter or deep brain stimulation electrode. Within this region of the brain that is going to be resected or transgressed, the research team will undertake a single-unit resolution neurophysiological recording (NR) using a digital neural probe (Neuropixels probe). Participants may have surgery done under general anaesthesia (“asleep”) or they may be awake during the surgery. This is determined by the type of surgery the participant is undergoing and is decided by their consultant neurosurgeon (outside of the remit of the research team). The research team will perform NR on both types of surgeries (asleep and awake), if deemed appropriate to do so. If participants are undergoing neurosurgery when awake, during the period of NR the patients may be asked to perform relevant neurological tasks (for example, undertaking particular movements, performing a cognitive test or looking at visual stimuli). These tasks will only be undertaken during surgery if deemed appropriate by the operating clinicians. Patients undergoing awake surgery will be asked to consent to these tasks prior to surgery. Participants' routine clinical standard of care and post-operative care will remain the same. There will be additional surgical steps required to capture the NR data for this study, including: Extension of planned surgery duration by up to 30 minutes for all participants who take part in this study. This means for asleep participants under general anaesthesia, anaesthetic time will be increased by up to 30 minutes. Within this time Neuropixels probe insertion, neurophysiological recording for up to 15 minutes, and Neuropixels probe removal. This 15-minute NR period is included within the total extended surgery time of up to 30 minutes (and not in addition to this). Procedure/Surgery The data sharing plans for the current study are unknown and will be made available at a later date. Data sharing statement to be made available at a later date 2cbbd112-563a-4227-bb6a-0de697bc5dd4 61e4c9e9-b7fc-481e-90de-cdf81a3d78e5 7c467312-a41d-4234-a315-e3d1dfb6d25b 930ca6c1-b00e-4919-b3c1-5d8bcadba023 No William Muirhead Scientific Principal investigator

The National Hospital for Neurology and Neurosurgery Queen Square

London United Kingdom WC1N 3BG +44 (0)2034567890 william.muirhead@crick.ac.uk Public Rachel McComish https://orcid.org/0009-0005-2846-2682 Public

The Comprehensive Clinical Trials Unit at UCL 90 High Holborn

London United Kingdom WC1V 6LJ +44 (0)20 7679 1287 cctu.sunan@ucl.ac.uk Public University College London University/education https://ror.org/02jx3x895 Non-commercial Francis Crick Institute http://dx.doi.org/10.13039/100010438