97585476 true A Phase Ib/IIa open-label dose-finding followed by randomized, double-blind, placebo-controlled expansion study to evaluate the safety, tolerability, and preliminary efficacy of TGD001 in patients with acute ischemic stroke TG1-CL-201 Primary objective: To assess the safety and tolerability of single intravenous (IV) doses of TGD001 in participants with an acute ischemic stroke (AIS) diagnosis, supported by neuroimaging, who either receive endovascular thrombectomy (EVT) or do not receive EVT or standard of care (SOC) intravenous thrombolysis (IVT). Secondary objectives: 1. To assess the rates of asymptomatic intracranial hemorrhage (aICH) 2. To determine the pharmacokinetic (PK) profile of single IV doses of TGD001 in participants with AIS 3. To assess recanalization post-intervention 4. To assess reperfusion post-intervention 5. To assess neurological outcome at 90 days post-intervention 6. To determine the functional status at 90 days post-intervention Background and study aims An acute ischaemic stroke happens when a blood clot blocks blood flow to part of the brain. This can damage brain tissue and may cause long-term disability. Current treatments include medicines that dissolve blood clots and a procedure to remove the clot, called thrombectomy. However, these treatments do not always work well enough, so better treatments are needed. This study is testing a new clot-dissolving medicine called TGD001. TGD001 targets a part of blood clots called von Willebrand factor, which is different from the main target of currently used clot-dissolving medicines. The main aim of the study is to find out whether TGD001 is safe and well tolerated in people who have had an acute ischaemic stroke. The study will also look at how TGD001 affects blood flow in the brain and recovery after stroke. Who can participate? Adults aged 18 years or older who have had an acute ischaemic stroke confirmed by a brain scan may be able to take part. This includes some people who have had a thrombectomy and some people who are not suitable for standard clot treatments. Men and women can take part, but women who are pregnant or breastfeeding cannot participate. What does the study involve? About 130 people will take part at specialist stroke hospitals. The study has two parts. In the first part, small groups of participants receive a single dose of TGD001 into a vein. Different doses are studied to help identify a suitable dose for further testing. In the second part, participants are randomly assigned to receive either TGD001 or a placebo treatment. Neither the participant nor most of the study team will know which treatment was given. Participants will continue to receive the standard stroke care that is appropriate for them. During the study, doctors will monitor participants for side effects. Participants will also have blood tests, brain scans and assessments of their stroke symptoms and ability to carry out everyday activities. Each participant will be followed for about 90 days. What are the possible benefits and risks of participating? Participants may or may not benefit directly from taking part. TGD001 may help dissolve blood clots and improve blood flow to the brain, but it is not yet known whether it will improve recovery from stroke. Participants will also be closely monitored during the study. The information collected may help researchers better understand TGD001 and may contribute to better treatments for people with stroke in the future. The main potential risk of TGD001 is bleeding, which may occur in the brain or elsewhere in the body. There is also a possibility of an allergic or treatment-related reaction. Blood tests, brain scans and other study procedures may also cause discomfort or carry small risks. Participants will be monitored and treated if any problems occur. Where is the study run from? The study is managed by TargED Biopharmaceuticals B.V. in Utrecht, the Netherlands. When is the study starting and how long is it expected to run for? March 2026 to December 2027 Who is funding the study? TargED Biopharmaceuticals B.V. (Netherlands) Who is the main contact? Sonja Visscher, clinops@targedbio.com 1. Symptomatic intracranial haemorrhage (sICH) is assessed according to the Heidelberg Bleeding Classification during the post-intervention follow-up (90 days) 2. Treatment-emergent adverse events (TEAEs) are assessed by standard adverse-event monitoring throughout the study follow-up period up to Day 90 1. Asymptomatic intracranial haemorrhage (aICH) is assessed by brain imaging during post-intervention follow-up (90 days) 2. Pharmacokinetics of TGD001 are assessed from plasma TGD001 concentrations and derived pharmacokinetic parameters, including Cmax, Tmax, AUC and t½, using serial blood samples collected at baseline and up to six timepoints 72 hours after treatment 3. Recanalization is assessed using computed tomography angiography (CTA) or magnetic resonance angiography (MRA) during post-intervention follow-up (90 days) 4. Reperfusion/perfusion deficit is assessed using computed tomography perfusion (CTP) or magnetic resonance perfusion (MRP) during post-intervention follow-up (90 days) 5. Neurological outcome is assessed using the National Institutes of Health Stroke Scale (NIHSS) during post-intervention follow-up and at Day 90 6. Functional outcome is assessed using the modified Rankin Scale (mRS) during follow-up and at Day 90 Ethics approval required

10.1186/ISRCTN97585476 1013913 TG1-CL-201 1013913 TG1-CL-201 Interventional Randomized controlled trial Blinded (masking used) Placebo Parallel Treatment Safety Not applicable Efficacy Safety Treatment Other 2027-12-31T00:00:00.000Z United Kingdom England Belgium France Germany Netherlands Poland Serbia Spain United States of America Royal Stoke University Hospital

Newcastle Road

Stoke-on-trent England ST4 6QG RJE01@2.16.840.1.113883.2.1.3.2.4.18.48 Kings College Hospital

Denmark Hill

London England SE5 9RS 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 University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Hamburg-Eppendorf

Martinistrasse 52

Hamburg Germany 20246 Klinikum Altenburg Land

Am Waldessaum 10

Altenburg Germany 4600 Universitätsklinikum Heidelberg

Im Neuenheimer Feld 400

Heidelberg Germany 69120 Klinikum Ernst von Bergmann

Charlottenstraße 72

Potsdam Germany 14467 Uniklinikum Dresden

Fetscherstraße 74

Dresden Germany 1307 Universitätsklinikum Bonn

Venusberg Campus 1

Bonn Germany 53127 Universitätsklinikum Tübingen

Hoppe-Seyler-Str. 3

Tübingen Germany 72076 Universitätsmedizin Charité

Hindenburgdamm 30a

Berlin Germany 12203 Hospital Universitario Virgen Macarena

Avenida Dr. Fedriani 3

Sevilla Spain 41008 Hospital Germans Trias i Pujol

Carretera de Canyet 8916, Badalona

Barcelona Spain Badalona Hospital Virgen de la Arrixaca

Caretta Madrid-Cartagena, El Palmar

Murcia Spain 30120 Hospital Álvaro Cunqueiro

Estrada de Clara Campoamor 341, Vigo

Pontevedra Spain 36312 Hospital Universitario Virgen del Rocío

Avenida Manuel Siurot

Sevilla Spain 41013 Hospital Universitari Vall d'Hebron

Pg. de la Vall d'Hebron, 119

Barcelona Spain 8035 Hospital Clínico Universitario de Valladolid

Avenida de Ramón y Cajal 3

Valladolid Spain 47003 Hospital Universitari de Girona

Avinguda de França

Girona Spain 17007 University Hospital in Krakow

Macieja Jakubowskiego 2

Krakow Poland 30-688 Górnoslaskie Centrum Medyczne im. Leszka

Gieca Slaskiego Uniwersytetu Medycznego w Katowicach ul. Ziołowa 45-47

Katowice Poland 40-635 Military Medical Academy

Crnotravska 17

Belgrade Serbia 11000 University Clinical Center Nis

dr Zoran Djindjic Boulevard 48

Nis Serbia 18000 University Clinical Center Kragujevac

Zmaj Jovina 30

Kragujevac Serbia 34000 University Clinical Centre of Vojvodina

Hajduk Veljkova 1

Novi Sad Serbia 21137 false 1. Age ≥18 years 2. Informed consent obtained from the participant or a participant representative in accordance with local legal and institutional review board (IRB) and independent ethics committee (IEC) requirements 3. Functionally independent (Modified Rankin Scale [mRS] 0-2) prior to stroke onset 4. Diagnosis of AIS supported by neuroimaging: 4.1. A visible occlusion on computed tomography angiography (CTA) or magnetic resonance angiography (MRA) imaging; and/or 4.2. An ischemic lesion ( Alberta stroke program early CT score [ASPECTS] 6 - 10) on non-contrast computed tomography (NCCT) or magnetic resonance imaging (MRI), with target mismatch on computed tomography perfusion (CTP) or magnetic resonance perfusion (MRP) imaging, if performed 5. National Institutes of Health Stroke Scale (NIHSS) ≥5 and that remains ≥5 immediately before enrollment 6. Participants who: 6.1. Meet the local endovascular thrombectomy (EVT) eligibility requirements and undergo EVT (Groups 1 and 2), or 6.2. Do not receive EVT or SOC IVT (Group 3) Mixed 18 Years 100 Years All 130 0 1. Unable to undergo both MRI and CT imaging 2. Intracranial hemorrhage on pre-intervention imaging 3. Demarcated infarct or early ischemic changes resulting in ASPECTS ≤5 on pre-intervention imaging 4. Active internal bleeding 5. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency 6. Use of an anticoagulant, including but not limited to direct oral anticoagulants (DOACs) or warfarin, within the last 48 hours or recent oral anticoagulant therapy with international normalized ratio (INR) ≥1.7. If the DOAC level is measured and found to be below the therapeutic threshold (Factor Xa inhibitor levels of less than 50 ng/ml or anti-Xa levels of less than 0.5 IU/ml), the participant can be enrolled regardless of the recency of the last dose. 7. Use of any medication and/or recent procedure that is known to significantly increase the bleeding risk (at the discretion of the investigator) 8. More than four recanalization attempts of target lesion with stent retriever or aspiration device during EVT prior to the use of the trial intervention 9. Coma, and/or NIHSS >25 10. Seizure(s) at stroke onset if this precludes obtaining an accurate baseline NIHSS 11. Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg). NOTE: If the blood pressure can be successfully reduced and maintained at an acceptable level using European Stroke Organization (ESO) guidelines-recommended medication (including i.v. antihypertensive drips), the participant can be enrolled. 12. Platelet count <100.000/µl 13. Blood glucose <50 mg/dl (2.8 mmol/l) or >400 mg/dL (22.20 mmol/l) 14. Impaired renal function as indicated by estimated glomerular filtration rate (GFR) below 30 ml/min/1.73 m² or requiring hemodialysis/peritoneal dialysis 15. Severe liver fibrosis or portal hypertension 16. Female who is pregnant, lactating, or has a positive pregnancy test at the time of admission 17. Evidence of active systemic infection that could have led to presumed septic embolus, suspicion of bacterial endocarditis 18. Surgery or trauma affecting intracranial or intraspinal areas within the last 2 months 19. Pre-existing severe medical, neurological, or psychiatric disease that would significantly confound the neurological or functional evaluations (investigator judgment) 20. History of cerebrovascular incident in the last 3 months 21. Intracranial neoplasm, arteriovenous malformation, or aneurysm 22. Other serious, advanced, or terminal illness in the last 3 months (investigator judgment) or life expectancy is less than 6 months 23. Known hypersensitivity to any of the trial treatments or their excipients or to drugs of similar chemical classes 24. Participant participating in a trial involving an investigational drug or device that would impact this trial within the last 30 days 2026-03-11T00:00:00.000Z 2027-12-06T00:00:00.000Z Acute ischemic stroke Circulatory System The trial consists of two parts and includes prespecified groups of participants with acute ischemic stroke. Phase 1b is an open-label, single-dose escalation and expansion phase. Participants receive one intravenous administration of TGD001. Dose-escalation and de-escalation decisions are overseen by the Data Safety Monitoring Committee (DMC), which will select the dose or doses for further evaluation. Three dose levels are planned for each patient group. Additional dose levels may be established by the DMC. Phase 2a is a randomized, double-blind, placebo-controlled expansion phase. Participants receive one intravenous administration of either TGD001 or placebo. Randomisation occurs before treatment according to a prespecified randomisation schedule. All participants are followed for approximately 90 days. Follow-up includes safety assessments, laboratory and pharmacokinetic/pharmacodynamic sampling, brain imaging, and neurological and functional outcome assessments. Drug Phase II TGD001 Data sharing statement to be made available at a later date db29f236-23c5-4f8b-aa3d-2a0291fbe736 10c7b714-113a-43d4-b301-c18cc55ef714 4a40f9a8-b842-4bf7-a462-f0767e8767b7 39daec96-d8ea-43b7-a53b-fbc6e870692d 29907399-4adf-4d09-b148-e286c697fc62 No Josefin-Beate Holz Scientific Public

Princetonlaan 6

Utrecht Netherlands 3584 CB +31 (0)30 2028079 ext 00 regulatory@Targedbio.com Public Sonja Visscher Scientific Public

Princetonlaan 6

Utrecht Netherlands 3584 CB +31 (0)30 2028079 ext 00 clinops@targedbio.com Public Christine Roffe Principal investigator

Guy Hilton Research Centre 1 Thornburrow Drive

Stoke-on-Trent United Kingdom ST4 7QB +44 (0)1782 679484 Christine.Roffe@uhnm.nhs.uk Public TargED Biopharmaceuticals B.V. Commercial TargED Biopharmaceuticals B.V. 15612522 true Regression in left ventricular hypertrophy and fibrosis in aortic stenosis – a randomised controlled trial (RELIEF-AS) RELIEF-AS To evaluate the effects of dapagliflozin, spironolactone, and their combination on myocardial hypertrophy, as measured by the indexed left ventricular mass post-AVR and assessed at 12 months post-randomisation, accounting for baseline, in patients with severe aortic stenosis treated by surgical AVR or TAVI. • Assess the impact of these interventions at 12 months post-randomisation on: o myocardial function (global longitudinal strain), o exercise capacity (6-minute walk test), o quality-of-life outcome (KCCQ, EQ-5D-5L). • Explore the safety and tolerability of these treatments in the post-AVR population. • Assess impact on outcome measures (All-cause mortality and cardiovascular mortality; heart failure hospitalisation; stroke and myocardial infarction; permanent pacemaker implantation). • Assess the mechanism of these interventions post-AVR, assessed at 12 months post-randomisation. • To assess myocardial fibrosis regression post-AVR, assessed at 12 months post-randomisation, as measured by cardiac MRI-derived indexed extracellular volume (iECV). In addition to iECV, other imaging measures of fibrosis, such as native T1 and ECV%, will be explored to understand the broader effects of dapagliflozin and spironolactone on the myocardium. Background and study aims Aortic stenosis is a condition in which the heart's main valve becomes narrowed, making it harder for blood to flow out of the heart. People with severe aortic stenosis often need either surgery or a minimally invasive procedure to replace the damaged valve. Although valve replacement can improve symptoms and help people live longer, some patients continue to experience damage to the heart muscle, which may increase their risk of heart failure and reduce their quality of life. Two medicines, dapagliflozin and spironolactone, are already used to treat heart failure and have been shown to improve heart health. Researchers want to find out whether these medicines can also help the heart recover after aortic valve replacement in people with severe aortic stenosis who do not have diagnosed heart failure. This study aims to determine whether dapagliflozin, spironolactone, or a combination of both medicines can improve recovery of the heart muscle after aortic valve replacement compared with standard care alone. Researchers will assess changes in heart structure, heart function, exercise capacity, quality of life and heart muscle scarring. Who can participate? Adult patients aged 18 years and over with severe aortic stenosis who are scheduled to undergo surgical or transcatheter aortic valve replacement and who meet the study eligibility criteria. What does the study involve? Participants will be randomly assigned to one of four groups to receive either dapagliflozin for 12 months, spironolactone for 12 months, a combination of dapagliflozin and spironolactone for 12 months or standard care without additional study medication. Participants will undergo assessments before starting treatment and again after 12 months. These assessments include MRI scans of the heart, echocardiograms, blood tests, questionnaires about quality of life, and a six-minute walking test. Additional safety monitoring will be carried out during the study to check kidney function and monitor for possible side effects of the medicines. What are the possible benefits and risks of participating? Participants may not experience direct health benefits from taking part. However, the medicines being studied may help the heart recover more effectively after valve replacement. The findings could lead to improved treatment for future patients with severe aortic stenosis. Possible risks include side effects related to the study medicines, such as dizziness, dehydration, genital infections, breast tenderness, nausea or raised potassium levels. Some participants may also experience temporary discomfort during blood tests or MRI scans. To reduce these risks, participants will receive regular monitoring and safety checks throughout the study. Where is the study run from? The study is sponsored by the Comprehensive Clinical Trials Unit at University College London and is being conducted in the UK. When is the study starting and how long is it expected to run for? The first participants are expected to be enrolled in December 2026. Recruitment is planned to continue until August 2028, and the study is expected to finish in February 2030. Who is funding the study? The National Institute for Health and Care Research (NIHR) UK. Who is the main contact? cctu.relief-as@ucl.ac.uk Left Ventricular Mass Index (LVMi) cardiac MRI in g/m2 baseline and 12 months post-randomisation Myocardial function ejection fraction, global longitudinal strain, and quantitative myocardial stress perfusion baseline and month 12 post-randomisation Myocardial fibrosis cardiac magnetic resonance (CMR) imaging combined with blood testing to assess indexed extracellular volume (iECV), native T1 and extracellular volume (ECV) baseline and month 12 post-randomisation Safety and tolerability of interventions from randomisation to 12 months post-randomisation the incidence of adverse events and participant clinical events reported on electronic Case Report Forms (CRF), collected the end of the study Efficacy assessed via quality of life, the Kansas City Cardiomyopathy Questionnaire and the EQ-5D-5L baseline, month 3, month 6, month 9 and month 12 post-randomisation Efficacy assessed via exercise capacity the 6-minute walk test baseline and month 12 post-randomisation Exploratory outcome: Pharmacodynamic effects of the interventions on myocardial stress and fibrosis standard laboratory methods to quantify biomarkers (NT-proBNP, collagen and hs-Troponin) baseline and month 12 post-randomisation Ethics approval required North of Scotland Research Ethics Service

Summerfield House

Aberdeen United Kingdom AB15 6RE 26/LO/0607 10.1186/ISRCTN15612522 1010996 NCT07539259 NCT07539259 1010996 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Safety Not applicable Efficacy Safety Treatment Other 2030-02-28T00:00:00.000Z United Kingdom England -

-

- England - false 1. Participants ≥ 18 years 2. Left Ventricular Ejection Fraction (LVEF) ≥40% 3. Diagnosed with severe aortic stenosis* by a cardiologist or cardiac surgeon. Severity of AS follows international guideline criteria, namely at least one of: 3.1. Effective orifice area [EOA] <1.0 cm2 3.2. Indexed EOA of ≤0.6 cm2/m2 3.3. Peak velocity ≥4.0 m/s or mean gradient >40 mmHg. * including severe low-flow, low-gradient AS 4. Referred for surgical or transcatheter AVR 5. Able to provide informed consent and comply with study procedures Mixed 18 Years 120 Years All 520 0 1. Current use, intolerance or hypersensitivity to MRAs or SGLT2 inhibitors 2. Hyperkalaemia (K>5.0 mmol/L) 3. Significant renal impairment (eGFR < 45 mL/min/1.73m²) 4. Severe hepatic insufficiency* 5. Concomitant severe other valve lesion (severe MR, MS or AR) 6. Contraindications to MRAs: 6.1. Addison's disease 6.2. Acute porphyrias 6.3. Receiving potassium-sparing diuretics, potassium supplements or strong inhibitors of CYP 3A4 (for example. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) 7. Contraindications to SGLT2-inhibitors: 7.1. Active urinary tract infections 7.2. At risk or with a history of diabetic ketoacidosis 8. Type 1 or Type 2 Diabetes on insulin 9. Concomitant diagnosis affecting trial participation or life expectancy of less than two years 10. Contraindications to MRI (e.g. non-conditional cardiac pacemaker, severe claustrophobia, inability to lie flat: participants who do not meet local safety rules for MRI). Conditional pacemakers/ICDs, if implanted after the baseline scan, are not an exclusion. 11. Ongoing participation in another CTIMP interventional clinical trial (i.e. drug trial), will not be permitted. Participation in any other trial will need to be discussed with the trial investigators. 12. Significant comorbidities that would contraindicate participation, including uncontrolled hypertension, or recent myocardial infarction (within 3 months prior to screening) 13. Pregnancy or breastfeeding, or females of childbearing potential not using an effective method of contraception 14. Any other medical or psychiatric condition that would interfere with participation or compliance with study procedures as determined by the Principal Investigator (PI) *As evidenced by features of decompensated cirrhosis e.g. hepatic encephalopathy, ascites, jaundice or markedly deranged liver blood tests e.g. elevated bilirubin, serum albumin <30 or deranged clotting 2026-12-01T00:00:00.000Z 2028-08-01T00:00:00.000Z Aortic stenosis Circulatory System Randomisation 1:1:1:1 via Sealed Envelope to either of: Arm 1 Dapagliflozin Oral tablet, 10 mg once daily, initiated post- randomisation and continued for 12 months Arm 2 Spironolactone Oral tablet, 25 mg once daily, initiated post- randomisation and continued for 12 months * Arm 3 Combination therapy: Dapagliflozin and Spironolactone. Oral dapagliflozin tablet 10 mg once daily, spironolactone 25 mg once daily, initiated post- randomisation and continued for 12 months * Arm 4 Control: Standard post-AVR clinical care. Routine NHS follow-up after AVR with no additional study drug. * Some patients on Spironolactone may experience nausea or gynaecomastia (~1/10 men) and will be switched to eplerenone 25 mg once daily in line with standard clinical practice. Drug Phase II Dapagliflozin, spironolactone, eplerenone Data sharing statement to be made available at a later date b321ec5c-a8fd-4ce6-9550-12936d93d0a5 fe42c47b-4873-4a2b-8eb0-b7ba0ee1d055 3949421b-7f6e-4825-94f4-1b57fc585600 39fbe8a6-fa5d-4a9c-85ae-b8535200a92d No CCTU trial team - Public

90 High Holborn

London United Kingdom WC1V 6LJ +44 (0)20 7670 ext 4781 cctu.relief-as@ucl.ac.uk Public Thomas Treibel Principal investigator Scientific

St Bartholomew’s Hospital

London United Kingdom EC1A 7BE - thomas.treibel.12@ucl.ac.uk Public Comprehensive Clinical Trials Unit at University College London https://ror.org/02jx3x895 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 18103637 true Examining the effectiveness, cost-effectiveness and mechanisms of 'Learning Together for Mental Health' on mental health outcomes: a nested, cluster randomised controlled trial in English secondary schools The study aim is to examine the effectiveness, cost-effectiveness and mechanisms of the 'Learning Together for Mental Health' (LTMH) whole-school intervention in terms of its mental health outcomes in a cluster randomised controlled trial and answer the following research questions: 1. What are the effects of LTMH in intention-to-treat (ITT) analyses on student-reported psychological difficulties (primary outcome), and various pre-hypothesised secondary mental health outcomes? 2. Are effects moderated by student baseline mental health, sex, gender, ethnicity, deprivation or sexual orientation, or school characteristics? 3. Are effects greater in analyses accounting for intervention fidelity? 4. What are the effects for pre-specified subgroups (students eligible for free school meals, students with higher reported psychological difficulties at baseline, student with non-white ethnicity, sexual minorities, girls and boys)? 5. Is the intervention cost-effective? 6. What do qualitative and quantitative data suggest about mechanisms by which the intervention generates mental health impacts? 7. What do the trial findings suggest about the intervention theory of change and transferability? Background and study aims Adolescence is an important period when many mental health problems emerge. These problems tend to worsen during secondary school. Poor mental health in adolescence can lead to problems such as self-harm, suicide, drug and alcohol dependence, poor school attendance and lower educational achievement. Mental health problems in adolescence can also have lasting effects for physical, social and mental wellbeing in adulthood. Programs in schools that target the context and culture, rather than individual students, are a promising way to improve student mental health. Some years ago, we tested such a program (called Learning Together) to reduce bullying in English secondary schools. We found that this program not only reduced bullying but also improved student mental health and GCSE results. We worked with the latest research, teachers and students, to adapt this program so it directly focused on mental health. We called it ‘Learning Together for Mental Health’ (LTMH). We also tested this new LTMH program in four secondary schools. We found it was well-liked and considered useful by teachers and students. An educational charity, the Education Endowment Foundation (EEF), is running large study with 140 schools to see if LTMH can improve educational achievement. We want to embed a mental health study, looking at effect of LTMH on mental health, in all these schools. EEF will not measure the mental health effect of LTMH as that is out-of-scope for them. It would represent very good value to also learn mental health effects within the same study. As a part of the mental health study, we aim to examine whether the LTMH program can improve student mental health, whether it works better for certain types of schools or students, and whether is offers a good value for money. We also aim to understand how it works, for whom and under what circumstances and how best it can be used in other settings, if needed. Who can participate? All state-funded, mainstream secondary schools in England can take part in the study so long as the senior leadership team is able to commit to participation for the whole duration of the program and pay the participation costs. What does the study involve? LTMH is a whole school program and involves training teachers to use a method call restorative practice. This differs from punishment-based methods by focusing instead on building relationships. It helps teachers model empathic conversation and manage conflict. The persons in a conflict can explain how they feel and take responsibility to find a way ahead. This helps heal relationships and prevents future problems. LTMH also involves setting-up of an ‘action group’ in each school, made up of teachers and students. Teacher and students work together to look at information collected from the students about their mental health alongside a manual with effective things to do for mental health. The action group then plan and make changes so the school feels more supportive. To study the impact of the program on student mental health, students in year-7 or year-8 in all 140 schools will fill-out a questionnaire about their mental health (this will be collected as a part of the EEF study). Through random choice, 70 schools will then get the LTMH program, while 70 will carry on with their normal approach. Schools that get the LTMH program will get staff training for restorative practice, support to deliver action groups and a manual. We will make sure LTMH is inclusive and accessible to all students. Three years later, students in all 140 schools (now in year-10) will fill-out a questionnaire again. We will compare results to see if students in the schools that got the LTMH program report better mental health. We will also look at how much the program costs, and talk to teachers and students about their thoughts on LTMH. This will help us know whether LTMH works, whether it’s good value for money and whether it could be used in secondary schools across the country. What are the possible benefits and risks of participating? If LTMH works, it could be used in schools across England to help improve mental health for thousands of young people. We will share our findings widely with schools, teachers, parents, students, charities, policymakers and the government to make sure they lead to real change. Participating schools will also get some financial compensation for taking part. Risks of participation are minimal but may include individuals feeling upset about something while completing the questionnaires or interviews. We have protocols in place to provide support to participants if this should happen. Where is the study run from? The mental health study is being led by a team of research from the London School of Hygiene & Tropical Medicine and University College London. The study of educational impacts of the LTMH programme is being done by a team of researchers from Anna Freud and Ipsos. When is the study starting and how long is it expected to run for? School recruitment for EEF’s large study on educational impacts began in March 2026 and is currently ongoing. The mental health study that we are embedding in this large study will use information collected from EEF’s study and will begin in September 2026. Who is funding the study? The embedded mental health study is funded by the National Institute of Health and Care Research, UK. The LTMH program is being funded by EEF as a part of their large study. Who is the main contact? Dr. Neisha Sundaram, London School of Hygiene & Tropical Medicine Psychological difficulties Strengths and Difficulties Questionnaire (SDQ) Total Difficulties score Year 10 through endline surveys Emotional problems, conduct problems, peer problems and hyperactivity SDQ subscales Year 10 through endline surveys Mental wellbeing Short Warwick-Edinburgh Mental Well-being Scale Year 10 through endline surveys Eating problems and weight and shape cognitions Eating problems and weight and shape cognitions (EDE-QS) Year 10 through endline surveys Bullying victimization Gatehouse Bullying Scale Year 10 through endline surveys Ethics approval required

10.1186/ISRCTN18103637 NIHR: 506643 506643 Interventional Randomized controlled trial Open (masking not used) Active Cluster Prevention Not applicable 2029-12-31T00:00:00.000Z United Kingdom England Schools in England

England

England England England true 1. State-funded, mainstream secondary schools in England 2. Senior leadership team (SLT) is able to commit to intervention, pay participation costs and sign Memorandum of Understanding (The impact evaluation will include students in year 7 for schools that completed baseline surveys in the summer term of 2026, or students in year 8 for schools that complete baseline surveys in the autumn term of 2026) Mixed 10 Years 70 Years All 140 0 1. The school’s most recent Ofsted rating is inadequate (based on the previous Ofsted grading). If the school has had an inspection since January 2026 with the new Ofsted grading criteria, schools that do not meet minimum safeguarding expectations and schools that receive an ‘urgent improvement’ grade in the ‘leadership and governance’ evaluation area will be excluded. Those schools will not be included, as the research has shown that schools require a minimum level of institutional capacity to implement the intervention. 2. The school is enrolled in another mental health or wellbeing intervention study. Note that schools involved in descriptive surveys or small pilot projects (e.g. with psychology students) will not be excluded 3. The school is enrolled in any other EEF trial currently that is also focused on mental health 4. The schools involved in the LTMH feasibility study 2026-03-02T00:00:00.000Z 2026-10-31T00:00:00.000Z Preventing mental health problems and improving wellbeing among secondary school students Mental and Behavioural Disorders This study involves a cluster randomised controlled trial (RCT) to examine the effectiveness, cost-effectiveness and mechanisms of the 'Learning Together for Mental Health' (LTMH) program in terms of its mental health outcomes for students, nested within the Education Endowment Foundation (EEF)'s trial assessing the impact of LTMH on educational outcomes. As part of the EEF trial, all pupils in Year 7 (Spring/Summer 2026) or Year 8 (Autumn 2026) in 140 schools will be invited to take part in an online survey completed in school. Schools are the unit of randomisation and are allocated on a 1:1 basis to the intervention and control arms, stratified by school-level factors: school-level deprivation (% students eligible for FSM below or above the median in England for the year); special education needs (SEN) status (proportion of students with SEN and disabilities); and attainment (Progress 8 score school average above and below median of 0 for England), by a researcher not involved in the statistical analysis from the Education Trial evaluation team. A first set of schools that completed ≥ 80% of responses on the baseline survey by the end of the summer term 2026 were randomised simultaneously in a block in late July 2026. Schools that complete their baseline surveys after this are being randomised on a weekly rolling (sequential) basis. Intervention: Learning Together for Mental Health (LTMH) is a whole-school, multicomponent, facilitated intervention that involves four key elements in each school. a) Formation of student and staff co-led Action Group (AG). It is empowered to modify school mental health and disciplinary policy. The AG will be facilitated by Place2Be staff. The AG will meet twice per term across each year of implementation, meeting more frequently if needed. The AG can draw on the following: (i) A student needs assessment report (NAR), drawing on the instruments and measures included in the baseline student survey. This provides the AG with data on their school’s prevalence of various needs, such as psychological problems, conduct problems, peer relationship problems, self-harm, eating problems, bullying, substance use and anti-social behaviour; (ii) An intervention manual including an evidence-based menu of effective mental health actions and strategies at the school level which have been previously shown to improve aspects of menatal health and wellbeing in young people. The Place2Be facilitator will guide the AG in using the menu and selecting actions from the menu that address the priorities identified for the school. The manual will also provide guidance on setting up and running inclusive AGs. b) Facilitation: The AGs are facilitated by a trained facilitator with expertise in school mental health, employed, supervised and trained by Place2Be. Place2Be will employ a lead facilitator who will manage and supervise these facilitators. Each school will receive seven half-day sessions of in-person facilitation in the first year of implementation and six sessions in the second year, supported by the same facilitator across the intervention. Online support from facilitators will be available to schools between in-person visits. In the third year of implementation, AG chairs will facilitate the AGs, supported by Place2Be where required. c) All-staff introductory training in restorative practice (RP) which aims to prevent and address conflict and thereby improve mental health via improving relationships. All staff are trained to implement primary RP through empathic communication and working ‘with’ students. d) In-depth training in RP for selected staff to facilitate meetings in which bullying victims are empowered to communicate harms, while perpetrators are encouraged to acknowledge these and take responsibility for their behaviour to repair relationships and prevent future conflict, thus contributing to improved mental health. The intervention will be a three-year programme, fully facilitated by Place2Be for the first two years and with light-touch support for schools from Place2Be in year 3. Schools will be encouraged to continue implementation independently in a fourth year, after which the educational evaluation will take place. Control: Control schools will continue their usual practice regarding existing relationships, sex and health education and mental health provision to maximise trial external validity A process evaluation (PE) will be conducted to explore mechanisms underlying mental health impacts and implementation. For this, in four case study schools, two staff members will be invited to participate in interviews every year for three years of the intervention. Students will also be invited to participate in two student focus groups per year of the intervention in each of the four case-study intervention schools. Behavioural Not expected to be made available ee405987-105e-4f45-b0f6-86d0687ed655 28327406-ca08-41d3-91c3-b26cc864b31d 1451ff06-9e7e-492e-a868-5682c9b8270f 254155fd-3877-47a0-b530-63e46bae3867 No Neisha Sundaram https://orcid.org/0000-0003-4159-9518 Principal investigator Public Scientific

15-17 Tavistock Place London School of Hygiene & Tropical Medicine

London United Kingdom WC1H 9SH +44 (0)20 7636 8636 neisha.sundaram@lshtm.ac.uk Public Russell Viner https://orcid.org/0000-0003-3047-2247 Principal investigator

University College London, UCL Great Ormond St. Institute of Child Health, UK, 30 Guilford St.

London United Kingdom WC1N 1EH +44 (0) 20 7679 2000 r.viner@ucl.ac.uk Public London School of Hygiene & Tropical Medicine https://ror.org/00a0jsq62 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 17201632 true Safety and Target Engagement of Transcranial Ultrasound Stimulation of the Ventral Intermediate Nucleus for Essential Tremor: A First-in-Patient Proof-of-Concept Study VIM-TUS-ET 1. To evaluate the safety and tolerability of transcranial ultrasound stimulation (TUS) targeting the ventral intermediate nucleus (VIM) of the thalamus in patients with essential tremor 2. To assess preliminary evidence of target engagement by evaluating whether TUS of the VIM produces measurable changes in tremor power compared with baseline and with sham stimulation Background and study aims Essential tremor is the most common movement disorder, causing involuntary shaking, most often of the hands, that can significantly affect daily life. Medication and surgery help many people, but a substantial proportion do not get adequate relief or cannot tolerate side effects. Transcranial ultrasound stimulation (TUS) uses low-intensity focused sound waves, delivered through the intact skull, to temporarily alter brain cell activity. It is non-invasive, and unlike established focused ultrasound treatments it does not destroy brain tissue. This study investigates whether TUS delivered by a helmet-shaped device called Meridian can safely target the ventral intermediate nucleus of the thalamus, a deep brain structure involved in controlling tremor, and whether stimulation produces any measurable change in tremor. This is a first-in-patient study; it is not designed to provide lasting tremor relief, and any effects are expected to be temporary. Who can participate? Men and women aged 18 to 80 years with essential tremor affecting both hands for at least 3 years, whose tremor medications have not worked adequately, have caused unacceptable side effects, or who prefer not to take them. What does the study involve? Participants attend a screening visit including a brain MRI scan, a single stimulation session lasting approximately 2.5 to 3 hours, and a telephone follow-up call the next day. During the stimulation session, participants sit in a chair wearing the Meridian device while small motion sensors on the hands measure tremor. Stimulation is delivered in four periods; one of the four is an inactive (sham) period, included so that any tremor changes can be attributed to the stimulation itself. Tremor is then monitored for up to 60 minutes. What are the possible benefits and risks of participating? Participants are not expected to receive any direct health benefit, but the results may help develop new non-invasive treatments for essential tremor. TUS has been used in research studies involving over 700 people with no serious adverse events reported. Possible side effects are mostly mild and short-lived, including headache, scalp discomfort or tingling, clicking or buzzing sounds during stimulation, and temporary changes in tremor. The MRI scan and device fitting may cause mild discomfort or claustrophobia. Where is the study run from? National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK When is the study starting and how long is it expected to run for? September 2026 to April 2027 Who is funding the study? NeuroHarmonics Ltd and UK Research and Innovation (UKRI) Who is the main contact? Dr Anna Latorre, a.latorre@ucl.ac.uk Safety adverse event and device deficiency recording (incidence, nature, severity, and relationship to device or procedure) each study contact from consent to the 24-hour follow-up (Visit 3) Target engagement (tremor modulation) log-transformed accelerometer-derived tremor band power (3-12 Hz) in the hand contralateral to the stimulated hemisphere, comparing the pre-stimulation baseline with the active stimulation and post-stimulation periods, pooled across the active conditions and compared with sham the single intervention session (Visit 2) Time course and durability of tremor modulation accelerometer-derived tremor amplitude 5-minute intervals for up to 60 minutes during the post-stimulation follow-up (Visit 2) Laterality of effect accelerometer-derived tremor amplitude in the ipsilateral hand (within-subject control) compared with the contralateral hand the intervention session (Visit 2) Clinical tremor severity the TETRAS Performance Subscale and Archimedes spiral drawing baseline and post-intervention (TETRAS), and after each stimulation condition and at 30 and 60 minutes during follow-up (spirals) (Visit 2) Participant experience and tolerability participant-reported sensations, a tolerability questionnaire, and the Patient Global Impression of Change the end of each stimulation condition and the end of the session (Visit 2), and the 24-hour telephone follow-up (Visit 3) Ethics approval required West of Scotland REC 3 (West of Scotland Research Ethics Service)

Admin Building, Level 2, Gartnavel Royal Hospital, 1055 Great Western Road

Glasgow United Kingdom G12 0XH 26/WS/0096 10.1186/ISRCTN17201632 365666 CPMS: 74798 365666 74798 Interventional Randomized controlled trial Blinded (masking used) Placebo Single Device feasibility Not applicable 2027-04-21T00:00:00.000Z United Kingdom England National Hospital for Neurology and Neurosurgery

Leonard Wolfson Experimental Neurology Centre, University College London Hospitals NHS Foundation Trust, Queen Square

London England WC1N 3BG false 1. Adults aged 18-80 years 2. Clinical diagnosis of essential tremor according to Movement Disorder Society consensus criteria 3. Tremor affecting both upper limbs, defined as TETRAS Performance Subscale item 4 (upper limb tremor) score >=1.5 in both upper limbs 4. Tremor duration of at least 3 years 5. Suboptimal response to, intolerance of, contraindication to, or preference not to use at least one first-line medication (propranolol, primidone) 6. Stable dose of tremor medication for at least 2 weeks prior to screening, or medication-naive 7. Able to maintain a postural hold position for tremor assessment (repeated blocks of 30 seconds) 8. Able to provide written informed consent, comply with study procedures, and communicate in English Mixed 18 Years 80 Years All 10 0 1. Any condition which results in significant movement of the head during a 30 second postural hold of the arms, including clinically apparent cervical dystonia, tics affecting the head, or head tremor (TETRAS Performance Subscale item 1 score >1) 2. Unable to achieve proper device fit due to head circumference exceeding 62 cm, or hair circumference exceeding 80 cm 3. Contraindications to MRI: 3.1. Metallic implants incompatible with MRI 3.2. Cardiac pacemaker or implantable cardioverter-defibrillator 3.3. Cochlear implants 3.4. Implanted medication infusion device (e.g., insulin pump, intrathecal pump) 3.5. Severe claustrophobia 3.6. Other standard MRI contraindications 4. Contraindications to transcranial ultrasound stimulation: 4.1. Previous cranial surgery or skull defects 4.2. Intracranial metallic implants, clips, or devices 4.3. History of epilepsy or unprovoked seizure 4.4. History of severe head trauma 4.5. History of unexplained syncope 4.6. Prior intracranial haemorrhage 4.7. Structural lesion at or near VIM target (tumour, cavernoma, AVM, large infarct) 4.8. Space-occupying lesion 4.9. Stroke (ischaemic or haemorrhagic in past 6 months) 4.10. MI (in past 6 months) and severe cardiac disease 4.11. Uncontrolled hypertension (systolic >180) 4.12. Current use of medications associated with a substantially increased seizure risk (clozapine or bupropion). Other medications with potential to lower seizure threshold will be reviewed at screening. Stable use of standard antidepressants and other psychotropic medications at usual therapeutic doses is permitted unless, in the opinion of the investigator, overall seizure risk is materially increased. 4.13. Electroconvulsive therapy (ECT) within the past 6 months 5. Pregnancy or breast-feeding 6. Previous surgical treatment for tremor (deep brain stimulation, thalamotomy, focused ultrasound ablation) 7. Other neurological conditions that could affect tremor assessment or confound results: Parkinson's disease; dystonia; multiple sclerosis; stroke affecting motor function; other movement disorders 8. Scalp condition that would prevent device placement (e.g., open wounds, severe dermatitis, psoriasis) 9. Recent scalp or cranial surgical procedure, biopsy, or hair transplant/follicle extraction within the past 6 months 10. Unable to tolerate sitting still for the duration of the intervention (approximately 120 minutes) 11. Participation in another interventional clinical trial within the past 30 days 12. Any condition that, in the opinion of the investigator, would make participation unsafe or compromise data quality 2026-09-21T00:00:00.000Z 2027-03-21T00:00:00.000Z Essential tremor Nervous System Diseases Participants receive a single session of low-intensity transcranial ultrasound stimulation (TUS), delivered with the Meridian device and targeting the ventral intermediate nucleus (VIM) of the thalamus in one hemisphere (left or right, randomised 1:1 using a computer-generated sequence). The session comprises four stimulation conditions, one of which is a sham (control) condition; participants are not told which condition is the sham. Hand tremor is measured by accelerometers during the session and for up to 60 minutes afterwards. Participants attend a screening visit including a brain MRI scan (Visit 1), the stimulation session lasting approximately 2.5 to 3 hours (Visit 2), and a telephone follow-up approximately 24 hours later (Visit 3); total participation is approximately 2 to 4 weeks. Device Not Applicable Meridian transcranial ultrasound stimulation system Not expected to be made available 41ac34fd-b381-4c8d-9ca3-9924bd1bc3e8 a311e742-a056-4445-83a5-2f1ace71aeb4 d3bafa5d-58f6-4c3c-a5e3-1af9325b6c7f 00914240-c656-4e67-b6f0-6c4b4b965125 No Anna Latorre Public Scientific Principal investigator

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square

London United Kingdom WC1N 3BG +44 20 3448 8066 a.latorre@ucl.ac.uk Public NeuroHarmonics Ltd Commercial NeuroHarmonics Ltd UK Research and Innovation http://dx.doi.org/10.13039/100014013 13555554 true Multinational real-world study of patients with HER2-positive biliary tract cancer treated with zanidatamab in an Early Access Program (RealiZe) RealiZe 1. To evaluate the real-world effectiveness of zanidatamab in patients with previously treated unresectable locally advanced or metastatic HER2-positive biliary tract cancer who received treatment through an Early Access Programme. 2. To characterise treatment patterns and utilisation of zanidatamab in routine oncology practice, including treatment duration, dose modifications, treatment interruptions and reasons for discontinuation. 3. To describe baseline demographic and clinical characteristics of patients receiving zanidatamab through the Early Access Programme, including disease characteristics, HER2 status, prior treatments and performance status. 4. To describe clinical outcomes following zanidatamab treatment, including tumour response, progression-free survival, overall survival, duration of response, time to next treatment and outcomes of subsequent anticancer therapies. Background and study aims Biliary tract cancer (BTC) is a rare and aggressive cancer affecting the gallbladder and bile ducts. Many patients are diagnosed when the disease is advanced and treatment options are limited. Zanidatamab is a medicine that targets HER2-positive cancers and has shown promising results in clinical trials. Before becoming widely available, some patients in the United Kingdom, Spain and Italy received zanidatamab through an Early Access Programme. This study aims to understand how zanidatamab is used and how effective it is in routine clinical practice by analysing information collected during normal patient care. Who can participate? Adults aged 18 years or older with previously treated unresectable locally advanced or metastatic HER2-positive biliary tract cancer who received at least one dose of zanidatamab through the Early Access Programme in the United Kingdom, Spain or Italy. What does the study involve? This is a retrospective observational study using existing medical records. No additional treatments, tests, procedures or study visits are required. Researchers will collect pseudonymised information from patient medical records, including demographic characteristics, medical history, cancer characteristics, details of zanidatamab treatment, tumour response, disease progression, subsequent treatments and survival outcomes. The information will be used to evaluate the real-world effectiveness of zanidatamab and to better understand how it is used in clinical practice. What are the possible benefits and risks of participating? Participants will not receive any direct medical benefit from taking part because no additional treatment or assessments are involved. However, the findings may improve understanding of zanidatamab and help inform future treatment decisions for patients with HER2-positive biliary tract cancer. The main risk is a potential loss of confidentiality. To minimise this risk, only pseudonymised data will be used for research purposes and identifiable information will remain securely protected at participating sites. Where is the study run from? The study is sponsored by Jazz Pharmaceuticals UK Ltd and is being conducted at participating cancer centres in the United Kingdom, Spain and Italy. When is the study starting and how long is it expected to run for? August 2026 to October 2026 Who is funding the study? Jazz Pharmaceuticals UK Ltd Who is the main contact? Prof. John Bridgewater, j.bridgewater@ucl.ac.uk Plain English summary under review with external organisation Real-world time on treatment (rwToT) the time from zanidatamab treatment initiation to treatment discontinuation for any reason, including physician-assessed disease progression, treatment-related toxicity, clinical decision, or death, derived from patient medical records and recorded in the electronic case report form (eCRF) the end of the available follow-up Real-world progression-free survival (rwPFS) the time from zanidatamab treatment initiation to physician-assessed disease progression or death from any cause, whichever occurs first, derived from patient medical records and recorded in the eCRF the end of the available follow-up Real-world subsequent-line progression-free survival (rwPFS2) the time from zanidatamab treatment initiation to physician-assessed disease progression following subsequent-line treatment or death from any cause, whichever occurs first, derived from patient medical records and recorded in the eCRF the end of the available follow-up Real-world overall survival (rwOS) the time from zanidatamab treatment initiation to death from any cause, derived from patient medical records and recorded in the eCRF the end of the available follow-up Real-world duration of response (rwDOR) the time from first documented physician-assessed partial response or complete response to disease progression or death, derived from patient medical records and recorded in the eCRF the end of the available follow-up Real-world objective response rate (rwORR) the proportion of patients achieving a physician-assessed complete response or partial response to zanidatamab treatment, based on medical record review and recorded in the eCRF the end of the available follow-up Patient demographics and relevant medical history demographic and clinical characteristics abstracted from medical records, including country of treatment, age at zanidatamab initiation, sex at birth, relevant comorbidities, date of biliary tract cancer diagnosis, HER2 test results, previous surgery, biliary tract cancer subtype, previous lines of treatment, ECOG performance status and participation in other interventional clinical trials baseline (zanidatamab treatment initiation) Dates of zanidatamab treatment initiation and discontinuation patient medical records and recorded in the eCRF the end of the available follow-up Zanidatamab dose, dose modifications and treatment interruptions patient medical records and recorded in the eCRF the end of the available follow-up Ethics approval required Health and Social Care Research Ethics Committee B (HSC REC B)

Office for Research Ethics Committees Northern Ireland (ORECNI) 2nd Floor James House, 2-4 Cromac Avenue

BELFAST United Kingdom BT7 2JA 26/NI/0041 Comité de Ética de la Investigación de la Fundación Jiménez Díaz (CEIm)

C/ del Maestro Ángel Llorca, 6 Bajo B, Edificio Alto

Madrid Spain 28003 EO093-26_FJD Comitato Etico Territoriale Lombardia 5

Via Alessandro Manzoni 56

Rozzano (MI) Italy 20089 436/26 10.1186/ISRCTN13555554 364497 CPMS: 70928, JZP598-527 364497 70928 JZP598-527 Observational Cohort study 2026-10-31T00:00:00.000Z United Kingdom England Italy Spain University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 Humanitas Cancer Center – IRCCS Humanitas Research Hospital

Via Manzoni 56

Rozzano (Milan) Italy 20089 IRCCS Candiolo Cancer Institute

Strada Provinciale 142 Km 3.95

Candiolo (Turin) Italy 10060 Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Via Giacomo Venezian 1

Milan Italy 20133 Hospital Universitario Fundación Jiménez Díaz

Avenida de los Reyes Católicos 2

Madrid Spain 28040 Vall d'Hebron Institute of Oncology

Calle Natzaret 115-117

Barcelona Spain 08035 Hospital Universitario 12 de Octubre

Avenida de Córdoba s/n

Madrid Spain 28041 false Patients with previously treated unresectable locally advanced or metastatic HER2-positive biliary tract cancer who received at least one dose of zanidatamab through the Early Access Programme (no upper age limit). In Spain and Italy, living patients must provide informed consent where required by local regulations. In the United Kingdom, eligible patients may be included using the approved opt-out process. Mixed 18 Years 99 Years All 42 0 United Kingdom only: Patients with an NHS National Data Opt-Out and patients who choose to opt out of participation. Spain and Italy: Patients who do not provide informed consent where consent is required by local regulations. 2026-08-03T00:00:00.000Z 2026-09-30T00:00:00.000Z HER2-positive biliary tract cancer (BTC), including unresectable locally advanced or metastatic disease Cancer This is a multinational, retrospective, longitudinal, observational cohort study conducted in the United Kingdom, Spain and Italy. Patients with previously treated unresectable locally advanced or metastatic HER2-positive biliary tract cancer who received at least one dose of zanidatamab through an Early Access Programme will be included. No treatments, interventions, study visits, tests, questionnaires or biological samples will be required as part of the study. Pseudonymised data will be collected retrospectively from existing medical records at participating cancer centres and entered into a standardised electronic case report form. Medical records covering medical history, zanidatamab treatment and subsequent follow-up will be reviewed. Data collected will include demographic and clinical characteristics, biliary tract cancer subtype, HER2 test results, ECOG performance status, relevant comorbidities, previous anticancer therapies, zanidatamab treatment details (including treatment dates, dose modifications, interruptions and reasons for discontinuation), concomitant medications, tumour response, disease progression, subsequent anticancer treatments and survival status. Real-world effectiveness outcomes assessed from medical records will include real-world time on treatment (rwToT), real-world progression-free survival (rwPFS), real-world subsequent-line progression-free survival (rwPFS2), real-world overall survival (rwOS), real-world duration of response (rwDOR), and real-world objective response rate (rwORR). Patients will be followed from initiation of zanidatamab treatment until treatment discontinuation, death, or the end of available follow-up. Drug Not Applicable Zanidatamab Not expected to be made available d6125dd4-bf84-4b3d-b7ca-a0087a87a658 a06a3318-fcc1-4690-b188-56796d9f6bc0 63d63342-3714-4c4a-8a65-c88f0d1707de 595f9d36-dbf8-4803-a64d-e9eaafb4e718 No John Bridgewater https://orcid.org/0000-0001-9186-1604 Principal investigator

University College London Hospitals NHS Foundation Trust JRO UCL, Gower Street

London United Kingdom WC1E 6BT +44 (0)20 3447 9093 j.bridgewater@ucl.ac.uk Public Sophie Thornton https://orcid.org/0000-0001-7693-7279 Scientific Public

Jazz Pharmaceuticals Ltd 80 Charlotte Street

London United Kingdom W1T 4DF +44 (0)20 3307 4847 Sophie.Thornton@jazzpharma.com Public Jazz Pharmaceuticals Ltd Commercial Jazz Pharmaceuticals http://dx.doi.org/10.13039/100011096 76569516 true A Phase IIIa randomised placebo-controlled biomarker enrichment trial: IgA2 anti-DNA antibodies as a biomarker of response to belimumab after rituximab in systemic lupus erythematosus STRATIFY lupus Primary objective: To determine whether clinical response, including prevention of disease flares through to 52 weeks, to belimumab after rituximab therapy is significantly superior to rituximab alone in lupus participants who are due to receive rituximab as part of their NHS standard of care and with high levels of serum IgA2 anti-dsDNA antibodies (≥12.5 AU). Secondary objective: To provide safety data, including the occurrence of infections and hypogammaglobulinemia for this combination in biomarker-positive participants during the 52-week trial duration. Background and study aims People with systemic lupus erythematosus (SLE) who are not responding to usual treatments like steroids are normally prescribed rituximab. STRATIFY lupus is based on a previous trial, BEAT-lupus, which showed that participants who were treated with belimumab after rituximab had fewer severe flares (worsening of symptoms) compared to treatment with rituximab alone. Autoantibodies are produced by the immune system in people with SLE and cause damage and inflammation to the body. Research on samples from BEAT-lupus participants identified an autoantibody called IgA2 anti-dsDNA that predicts which SLE patients may respond better to the combination treatment of rituximab followed by belimumab. Who can participate? Patients aged 16 to 75 years with active SLE who are not responding to standard treatment, are being considered for rituximab, and are positive for the IgA2 anti-dsDNA antibody. What does the study involve? Participants will be randomly allocated to either group A, belimumab intravenous (IV) infusions after rituximab for 48 weeks or group B, placebo IV infusions after rituximab treatment for 48 weeks. Participants will be in the study for a total of 52 weeks. The trial is ‘double blind’, meaning neither the participant nor the trial team will know which group the participant has been randomly allocated to. Participants will attend face-to-face visits, including an IV infusion every 2 weeks and then every 4 weeks until week 48. The final visit at week 52 does not include an IV infusion. Participants will undergo pre-specified assessments, complete questionnaires, and may have optional research blood and stool samples collected. What are the possible benefits and risks of participating? A positive trial will help to ensure access to rituximab followed by belimumab for those people who are most likely to respond and improve our understanding of SLE as a result. The most frequently reported adverse reactions for systemic lupus erythematosus (SLE) patients who are treated with belimumab are infection and delayed onset of symptoms of acute hypersensitivity reactions. Participants will be closely monitored after their first and second infusions for a minimum of 3 hours by the site research team. This is because symptoms of hypersensitivity occur more frequently during the first two infusions and then tend to decrease. If necessary, site teams can monitor participants for an extended period at all trial visits. At every trial visit, adverse events will be reviewed by the site research team for any updates, and recurring adverse events or resolutions will be recorded. Any participants with recurring infections or adverse events may be asked to stop trial treatment and/or withdraw from the trial for their own safety. Participants will be informed of all adverse events associated with belimumab and symptoms to look out for. They will also be provided with a card containing contact details for their research team that can be used 24 hours a day, 7 days a week. If necessary, emergency unblinding can also take place 24 hours a day, 7 days per week. The trial location teams will be aware of the risk of these adverse events and provided with the relevant safety information for Belimumab alongside the protocol. When participants experience flares or symptoms such as photosensitivity, extreme fatigue or joint pain, travelling to trial visits may become difficult, especially for elderly participants. Additionally, younger participants may have other obligations, such as employment or education, which can make trial visits inconvenient. The trial has been designed to minimise the travel burden through only visits 1, 2 and 3 being every 2 weeks; from visit 4 onwards, each visit is every 4 weeks. There are also no additional trial activities for participants to complete outside of the scheduled face-to-face visits. Participants will be informed of the visit schedule, what to expect at each visit and the approximate time for a visit in the participant information sheet. There is an allowance of +/- 3 days for the 2- weekly scheduled treatment visits and +/- 7 days for the 4- weekly scheduled treatment visits, as well as a 4-8 week window from the first screening visit to randomisation. Participants who are under the age of 18 years old may find it uncomfortable to complete the scheduled urine pregnancy testing, discuss contraception or complete questionnaires in the presence of their parents/legal guardians. The participant information sheet has a summary of the visit schedule, outlines what to expect at each visit and the requirement for urine pregnancy testing and contraceptive use. Special attention and care will be given to the “sexually active” prompt in participants, as per the clinician's discretion and only if appropriate to do so. The clinicians will ensure there is a safe space at visits to discuss these matters where appropriate. Participants will be given the opportunity to discuss such matters in a private environment. Biological samples will be shipped to the UCL Department of Medicine at the Rayne Building (Ehrenstein Laboratory) at specified timepoints as per the protocol. There is a risk that these samples get lost when transported. A Sample Management Plan will be followed and provided to sites, there will be full accountability logs for each sample from the point of collection, storage and transfer. Oversight logs will be maintained at sites and reviewed during monitoring and requested for central monitoring by the CCTU. There is limited data on the effects of belimumab on pregnancy. Participants of childbearing potential must either use a form of contraceptive with a failure rate <1% or be sexually inactive by abstinence. These participants must have a negative serum or urine pregnancy test at screening and will have regular urine pregnancy tests at each trial visit before treatment. Participants who are pregnant, breastfeeding or plan to become pregnant either during the trial period or within 4 months of trial treatment stopping will not be eligible for the trial. Any pregnancies that occur from consent to within 4 months of the last dose of trial treatment must be reported to UCL CCTU for follow-up and trial treatment stopped accordingly as applicable. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? November 2026 to November 2029 Who is funding the study? 1. Arthritis UK 2. NIHR Efficacy and Mechanism Evaluation Programme (EME) (UK) Who is the main contact? STRATIFY lupus trial team, cctu.stratifylupus@ucl.ac.uk Modified Major Clinical Response (MCR) at 52 weeks. Modified MCR is defined as a reduction in BILAG–2004 (British Isles Lupus Assessment Group-2004) index A/B scores to BILAG–2004 C/D or remain E in all domains, a reduction in steroid dose to ≤7.5 mg daily and a modified SLEDAI (Systemic Lupus Erythematosus Disease Activity Index 2000) –2K score ≤2 (without including the IgG anti-dsDNA antibody component) and no increase in immunosuppressant dose in the last 3 months before 52 weeks. 1. Modified Major Clinical Response (MCR) at 24 weeks: Reduction in BILAG–2004 (British Isles Lupus Assessment Group-2004) index A/B scores to BILAG–2004 C/D or remain E in all domains, a reduction in steroid dose to ≤7.5 mg daily and a modified SLEDAI (Systemic Lupus Erythematosus Disease Activity Index 2000) –2K score ≤2 (without including the IgG anti-dsDNA antibody component). 2. Major Clinical Response (MCR) at 24 and 52 weeks: Reduction in BILAG–2004 (British Isles Lupus Assessment Group-2004) index A/B scores to BILAG–2004 C/D or remain E in all domains, a reduction in steroid dose to ≤7.5mg daily and a modified SLEDAI (Systemic Lupus Erythematosus Disease Activity Index 2000) –2K score ≤4. For the 52- week outcome: no increase in immunosuppressant in the last 3 months. 3. Time to first incidence of: 3.1. Severe BILAG-2004 A flare (severe flare: a BILAG-2004 A score due to items which are “new” or “worse”; or, in the renal or haematological systems, an A score due to items which didn’t result in an A score last month). 3.2. Severe or moderate BILAG-2004 flares (moderate flare: 2 BILAG-2004 B scores due to items which are either “new” or “worse”; or, in the renal or haematological systems, B scores due to items which didn’t result in a B score last month) accompanied by an increase in concomitant lupus medication: glucocorticoids, or immunosuppressant through to 24 and 52 weeks. 3.3. Severe or moderate BILAG-2004 flare (moderate flare: 2 BILAG-2004 B scores due to items which are either “new” or “worse”; or, in the renal or haematological systems, B scores due to items which didn’t result in a B score last month). 3.4. BILAG-2004 low disease activity with prednisolone i) ≤5 mg/day (BILAG-2004 LDA-5); ii) ≤7.5 mg/day (BILAG-2004 LDA-7.5), and stable dose of immunosuppressive drugs. 4. Time to achieve: 4.1. BILAG-2004 low disease activity with prednisolone i) ≤5 mg/day; ii) ≤7.5 mg/day and stable dose of immunosuppressive drugs 4.2. Lupus Low Disease Activity State (LLDAS) 4.3. DORIS (Definition of Remission in SLE) remission 5. Proportion of patients at 24, 36 and 52 weeks in: 5.1. BILAG-2004 low disease activity with prednisolone: i) ≤5 mg/day; ii) ≤7.5 mg/day and stable dose of immunosuppressive drugs 5.2. DORIS remission 5.3. LLDAS 6. Cumulative steroid and immunosuppressant doses during treatment from randomisation to 52 weeks measured using case report forms 7. Impact of SLE and the trial treatment measured using Lupus Quality of Life (LupusQoL), SF-36 and EQ5D at 52 weeks 8. IgA2 anti-dsDNA antibody levels measured using ELISA assay at 24 and 52 weeks 9. Proportion of participants with any infectious serious adverse event through to week 52 of the trial. 10. Proportion of participants with any adverse events and proportion with any serious adverse events through to week 52 of the trial. 11. Total serum IgG levels measured using standard automated immunoturbidimetric assay at 52 weeks. Ethics approval required East of England - Cambridge East Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom EC20 1JQ 26/EE/0155 10.1186/ISRCTN76569516 1013219 CPMS: 57705, 160445 1013219 57705 160445 Interventional Randomized controlled trial Blinded (masking used) Placebo Parallel Treatment Not applicable Efficacy Safety Treatment 2029-11-30T00:00:00.000Z United Kingdom England Wales University College London Hospital

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal Glamorgan Hospital

Ynysmaerdy

Pontyclun Wales CF72 8XR 7A5B1@2.16.840.1.113883.2.1.3.2.4.18.48 Manchester Royal Infirmary

Oxford Road

Manchester England M13 9WL RM326@2.16.840.1.113883.2.1.3.2.4.18.48 King's College Hospital

Denmark Hill

London England SE5 9RS Guy's and St Thomas' Hospitals

Trust Offices Guy's Hospital Great Maze Pond

London England SE1 9RT RJ100@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Free Hospital

Royal Free Hospital Pond Street

London England NW3 2QG Royal Hallamshire Hospital

Glossop Road

Sheffield England S10 2JF TAH73@2.16.840.1.113883.2.1.3.2.4.18.48 Doncaster Royal Infirmary

Armthorpe Road

Doncaster England DN2 5LT RHQDR@2.16.840.1.113883.2.1.3.2.4.18.48 Sandwell General Hospital

Lyndon

West Bromwich England B71 4HJ RRK91@2.16.840.1.113883.2.1.3.2.4.18.48 Mile End Hospital

Block 9 Me67 275 Bancroft Road

London England E1 4DG V14969@2.16.840.1.113883.2.1.3.2.4.18.48 Royal United Hospital

Combe Park

Bath England BA1 3NG RVNG4@2.16.840.1.113883.2.1.3.2.4.18.48 Chapel Allerton Hospital

Chapeltown Road

Leeds England LS7 4SA RGD21@2.16.840.1.113883.2.1.3.2.4.18.48 Freeman Road Hospital

Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTR52@2.16.840.1.113883.2.1.3.2.4.18.48 Addenbrooke's Hospital

Hills Road

Cambridge England CB2 0QQ RGT01@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital

Queen Elizabeth Hospital Edgbaston

Birmingham England B15 2TH Southampton

Southampton General Hospital Tremona Road

Southampton England SO16 6YD NV513@2.16.840.1.113883.2.1.3.2.4.18.48 Broadgreen Hospital

Thomas Drive

Liverpool England L14 3LB RBN59@2.16.840.1.113883.2.1.3.2.4.18.48 Nuffield Orthopaedic Centre

Windmill Road Headington

Oxford England OX3 7HE RTH03@2.16.840.1.113883.2.1.3.2.4.18.48 Aintree Hospitals

Liverpool University Hospitals Longmoor Lane

Liverpool England L9 7AL false 1. Aged between 16 and 75 years inclusive at screening. 2. Participants who meet the 2019 criteria for SLE according to the European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. 3. Positive serum IgA2 anti-dsDNA antibodies (≥12.5 AU) at time of screening measured in UCL laboratory. IgA2 results defined in UCL Central laboratory. 4. Participants are due to be treated with the first infusion of B-cell depletion therapy (e.g. Rituximab) 4-8 weeks before randomisation (Day 0, see participant timeline) for active SLE. Previous use of rituximab is allowed prior to this cycle. 5. No contraindications to the use of belimumab. 6. Participants willing and able to provide informed consent. Mixed 16 Years 75 Years All 66 0 1. Pregnant or planned pregnancy during the trial and/or breastfeeding. 2. Women of childbearing potential (WOCBP) not willing to use highly effective contraception or abstinence for the duration of the trial and for at least 4 months following the last dose of the study drug. 3. Prior use of biologic/advanced therapy (except rituximab given as part of this trial after screening) less than 3 months before randomisation. 4. Participation in any other interventional trial within the last 6 months before randomisation. 5. eGFR <30 ml/min at screening 6. Active infections, including but not limited to: 6.1. Current or past infection with hepatitis B or C as defined by: 6.1.1. Hepatitis B surface antigen positive 6.1.2. Hepatitis B surface antibody positive and hepatitis B core antibody positive 6.1.3. Hepatitis C antibody positive 6.2. Historically positive HIV test or test positive at screening for HIV 6.3. Active TB 7. Infection history: 7.1. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) 7.2. Hospitalisation for treatment of infection within 30 days prior to randomisation 8. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 30 days prior to randomisation. 9. Receipt of a live-attenuated vaccine within 3 months prior to randomisation. 10. In the investigator’s opinion, participants that are at high risk for infection (including but not limited to in-dwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent severe urinary tract infection). 11. Primary immunodeficiency. 12. History of malignant neoplasm within 5 years prior to randomisation except for basal cell carcinomas of the skin, squamous cell carcinomas of the skin, and carcinoma in situ of the cervix that have been completely excised and considered cured for >2 years prior to screening. 13. History of cervical dysplasia CIN Grade III cervical high risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) in the last 3 years prior to randomisation. The participant will be eligible after the condition has resolved (e.g., follow-up HPV test is negative, or cervical abnormality has been effectively treated >1 year ago). 14. Severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, pulmonary, cardiac, or neurological disease or, in the investigator’s opinion, any other concomitant medical condition or significant abnormal laboratory value that places the participant at risk by participating in this study except for diseases or conditions related to active SLE. 15. Comorbidities not lupus related currently requiring systemic corticosteroid or immunosuppressant therapy. 16. Evidence of serious suicide risk including having any history of suicidal behaviour in the last 6 months and/or suicidal ideation in the last 2 months, or who in the investigator’s judgement, pose a significant suicide risk. 17. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. 18. IgG levels <4.0 g/L or IgA level <1 mg/dL tested no more than 10 days before randomisation. 19. White blood cells (WBC) <1.5 x 10e9/L or Neutrophils <1.0 x 10e9/L measured no more than 10 days before randomisation. 20. Current drug or alcohol abuse or dependence or a history of drug or alcohol abuse or dependence within a year prior to randomisation. 2026-11-01T00:00:00.000Z 2028-10-31T00:00:00.000Z Systemic lupus erythematosus Skin and Connective Tissue Diseases Participants will be randomised to receive belimumab or placebo (normal saline, sodium chloride 0.9%) using Sealed Envelope. Intravenous administration of belimumab or placebo will be given from randomisation at the recommended standard dosage and intervals: 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter for 48 weeks. The final assessment visit will occur at week 52. After the first Screening visit, participants will have their first and second rituximab infusion and their eligibility for the trial confirmed during the second Screening and Randomisation visit. During each visit at their trial location, participants will have any medications they are taking reviewed; a physical exam and urine test; vital signs and weight change check; blood samples taken for safety monitoring; complete questionnaires about their lupus activity and how they feel during the trial and the collection of optional blood and stool samples. Drug Phase III Belimumab Data sharing statement to be made available at a later date

293f19f9-c2bb-4acf-8e4b-dad65096166a 2f1109d7-e7da-4206-80e4-830fc9f0e012 612b4321-391d-4634-9085-f039f0793a4e 1f1c359e-3c20-4590-a36d-1cd7a0282bc9 56f65825-e769-4566-8e0a-6ff14b7f1294 No Participant information sheet 48873_PIS_V1.0_11Dec2025.pdf cde03ae1-25d9-4584-953c-060781b774d1 true application/pdf 355593 3c012ed710bb938edbdf45aaa6401e7e Participant information sheet ISRCTN76569516_PIS_V2.0_29Jul2026.pdf 694c2e75-d182-45d5-95f8-778b8fb14974 true application/pdf 371626 0264bc631a3caa867a02093b9e070246 Michael Ehrenstein Principal investigator Scientific

University College London, 4th Floor, Room 418, Division of Medicine, 5 University Street

London United Kingdom WC1E 6JF +44 (0)20 3447 9035 m.ehrenstein@ucl.ac.uk Public STRATIFY lupus Trial Team Public

Comprehensive Clinical Trials Unit at UCL 90 High Holborn

London United Kingdom WC1V 6LJ - cctu.stratifylupus@ucl.ac.uk Public University College London https://ror.org/02jx3x895 Non-commercial Arthritis Research UK http://dx.doi.org/10.13039/501100000341 Efficacy and Mechanism Evaluation Programme http://dx.doi.org/10.13039/501100001922 10183174 true A combined laryngeal and respiratory approach to presbyphonia voice therapy: feasibility trial (CLEARER) CLEARER - Feasibility Trial Primary objective: To assess feasibility and acceptability of the CLEARER Voice Group intervention content and delivery to participants and clinicians Secondary objectives: 1. To assess the feasibility of recruiting adults ≥50 years with ENT-confirmed presbyphonia into the trial 2. To assess the feasibility of adequate dosing of the intervention (participant attendance) given its group delivery context 3. To examine adherence to home practice 4. To examine the fidelity with which clinicians deliver the intervention as specified 5. To determine the acceptability and feasibility of the data collection procedure 6. To explore clinician experiences of delivering the intervention, including perceived barriers and facilitators to implementation 7. To explore participant experiences of receiving the intervention, including perceived relevance, burden, and utility 8. To describe changes in clinical outcomes over the course of the intervention, without drawing conclusions about effectiveness 9. To assess the suitability and acceptability of proposed clinical outcome measures for use in a future trial 10. To identify refinements needed to optimise the intervention, trial procedures, and trial design for a future evaluation Background and study aims As people get older, changes can occur in the voice and breathing systems that make the voice sound weak, breathy, quiet, or effortful. This condition, known as presbyphonia (age-related voice disorder), can affect communication, confidence, social activities, and quality of life. Current voice therapy mainly focuses on the voice box (larynx), but recent research suggests that age-related changes in breathing may also play an important role. The CLEARER study aims to find out whether a new group-based voice therapy programme that combines breathing and voice exercises is practical and acceptable to deliver in NHS services, and whether it should be tested further in a larger study. Who can participate? Adults aged 50 years and over who have been diagnosed with presbyphonia (an age-related voice disorder) by an Ear, Nose and Throat (ENT) specialist and who are able to take part in English-language group discussions and activities may be eligible to participate. Some people will not be eligible, including those with certain neurological conditions, other voice disorders, recent voice therapy, significant hearing or cognitive difficulties, or medical conditions that would make some of the breathing assessments or exercises unsuitable. What does the study involve? Participants will attend an initial visit at University College London Hospitals (UCLH), where they will provide consent, complete screening checks, questionnaires, and voice and breathing assessments. They will then attend six group therapy sessions at their local NHS site over approximately three months. The sessions include education about voice and breathing, voice exercises, breathing training, and conversation practice. Participants will also be asked to complete home practice between sessions. After completing the programme, participants will return to UCLH for repeat assessments and provide feedback about their experiences of the study and the therapy programme What are the possible benefits and risks of participating? Participants may find that the programme helps them better understand and manage their voice, improves their confidence when communicating, and provides support from meeting others with similar voice difficulties. However, these benefits cannot be guaranteed. Risks are considered low and are similar to those associated with routine speech and language therapy. Some participants may experience temporary vocal fatigue, mild throat discomfort, or brief light-headedness during voice or breathing exercises. Attending appointments and completing home practice may also require time and effort. Participants can withdraw from the study at any time without affecting their usual care. Where is the study run from? The study is coordinated by University College London Hospitals NHS Foundation Trust (UCLH). The group therapy programme will be delivered at four NHS sites in London: UCLH, Guy's and St Thomas' NHS Foundation Trust, Imperial College Healthcare NHS Trust (Charing Cross Hospital), and Whittington Health NHS Trust. Specialist assessment visits will take place at UCLH. When is the study starting and how long is it expected to run for? September 2026 to June 2027 Who is funding the study? The National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Brian Saccente-Kennedy, brian.saccente-kennedy@nhs.net Patient and clinician acceptability of intervention the Theoretical Framework of Acceptability Questionnaire post-treatment 1. Recruitment rate measured using the percentage of eligible participants who provide informed consent and are enrolled in the trial at pre-treatment 2. Intervention dose received measured using the percentage of recruited participants who attend at least 5 of 6 CLEARER Voice Group sessions recorded in attendance logs at post-treatment 3. Acceptability of trial procedures measured using the Modified Theoretical Framework of Acceptability Questionnaire at post-treatment 4. Clinician treatment fidelity measured using the percentage of prescribed session components delivered by each treating clinician recorded in clinician fidelity records at post-treatment 5. Adherence to home practice measured using the percentage of prescribed daily home practice completed by participants recorded in home practice tracking logs from session 2 to session 6 6. Group climate measured using the Group Climate Questionnaire Short Form (GCQ-S) at post-treatment 7. Voice-related quality of life measured using the Aging Voice Index (AVI) at pre-treatment and post-treatment 8. Self-rated voice function measured using visual analogue scales at pre-treatment and post-treatment 9. Vocal tract discomfort measured using the Vocal Tract Discomfort Scale (VTDS) at pre-treatment and post-treatment 10. Voice quality measured using the Acoustic Voice Quality Index (AVQI) at pre-treatment and post-treatment 11. Perceptual voice severity measured using the Overall Severity domain of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) at pre-treatment and post-treatment 12. Speech breathing kinematics measured using lung volume initiation (LVI) during extemporaneous speech at pre-treatment and post-treatment 13. Laryngeal aerodynamics measured using laryngeal resistance; glottal airflow; estimated subglottic pressure at pre-treatment and post-treatment 14. Respiratory muscle strength measured using maximum inspiratory pressure (MIP); maximum expiratory pressure (MEP) at pre-treatment and post-treatment 15. Laryngeal status measured using bowing index (BI), normalised glottic gap (NGGA), medial compression at pre-treatment and post-treatment Ethics approval required London - City & East Research Ethics Committee

Research Ethics Committee Centre, 2nd Floor, 2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/LO/0507 10.1186/ISRCTN10183174 369432 CPMS: 73274, NIHR: 303555 369432 73274 303555 Interventional N/A: single arm study Open (masking not used) Uncontrolled Single Treatment Not applicable 2027-06-01T00:00:00.000Z United Kingdom England University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 Guy's and St Thomas' NHS Foundation Trust

St Thomas' Hospital Westminster Bridge Road

London England SE1 7EH RJ1@2.16.840.1.113883.2.1.3.2.4.18.48 Imperial College Healthcare NHS Trust

The Bays St Marys Hospital South Wharf Road

London England W2 1BL RYJ@2.16.840.1.113883.2.1.3.2.4.18.48 Whittington Health NHS Trust

The Whittington Hospital Magdala Avenue

London England N19 5NF RKE@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. 50 years of age or older 2. ENT consultant-confirmed diagnosis of presbyphonia 3. Laryngeal images from most recent (within 6 months) ENT exam available for analysis 4. Typical hearing (as indicated by hearing screening at 40 dB HL at 500, 1000, and 1500 Hz, bilaterally), wearing hearing aids (if applicable) 5. Comfortable using spoken English in a group conversation setting 6. Willing and able to provide informed consent Mixed 50 Years 120 Years All 16 0 1. Recent (< 12 months) voice therapy 2. Current diagnosis of a neurological condition affecting laryngeal or respiratory function (i.e., Parkinson’s disease, CVA, spasmodic dysphonia) 3. Current diagnosis of additional laryngeal pathology 4. Contraindicated for spirometry (haemoptysis of unknown origin, pneumothorax, unstable cardiovascular status, ‘recent’ (< 6 weeks) myocardial infarction or pulmonary embolus , thoracic/abdominal/cerebral aneurysms, ‘recent’ (<6 weeks) eye surgery, nausea/vomiting, ‘recent’ (<6 weeks) thoracic/abdominal surgery) 5. Contraindicated for PEEP (haemodynamic instability (caused by cardiogenic shock, recent myocardial infarction, left heart failure, hypovolaemia), severe hypotension, severe COPD/asthma, raised intracranial pressure, diagnosis of an air leak syndrome (i.e., bronchopleural fistula) or unilateral lung disease) 6. Failing cognitive screen (scoring <23 on the Rowland Universal Dementia Assessment Scale [RUDAS]) 2026-09-01T00:00:00.000Z 2026-10-31T00:00:00.000Z Presbyphonia Signs and Symptoms This study is a non-randomised multicentre feasibility trial of CLEARER Voice Group mechanisms of action. The trial will run at UCLH and three additional NHS sites (Guy's Hospital, Charing Cross Hospital, and Whittington Hospital). These sites were selected because they already have awareness of the CLEARER project, established ENT/SLT services, and the specialist staff and equipment required to deliver the intervention safely and consistently. Baseline and outcome measurements will be conducted at UCLH, where specialist acoustic, aerodynamic, and perceptual assessment facilities are available. Pre- and post-intervention measures: Potential participants will be identified from SLT/ENT clinics or lists of patients referred to SLT teams and currently awaiting input for presbyphonia across the four study sites. Despite the use of multiple sites, consenting, screening, and registration will all occur centrally at UCLH during a consenting and baseline data collection appointment. Following informed consent, potential participants who pass an initial hearing and cognitive screen will undergo an approximately 75-minute baseline data collection session at UCLH. During this session, baseline data will be collected by the CI, who has the specialist training and equipment required. Participants will then return to their home study site to undergo CLEARER Voice Group treatment (see below). Once the treatment block has been completed, they will return to UCLH for repeat data collection and an exit interview. Group structure: Each site will deliver one block of six group sessions, each lasting approximately 90 minutes, with 3 to 5 participants per group. The CLEARER Voice Group is a structured, progressive programme combining: 1. High-resistance semi-occluded vocal tract training 2. Respiratory lung volume training, including incentive spirometer-guided breath work 3. Conversation Training Therapy, including clear speech, prosody, projection, and negative practice 4. Sensory discrimination and error-detection training 5. Real-world conversational practice The intervention is cumulative. Early sessions focus on rapport, education, and motor training; later sessions emphasise spontaneous conversation, self-monitoring, and generalisation. Therapy sessions Every session follows a consistent structure: 1. Check-in and normalisation: Participants briefly reflect on their voice since the previous session. Clinicians normalise variability. 2. Review of the previous session's content. 3. Introduction of new intervention content: Each session includes structured exercises delivered in whole-group, dyad, and individual formats. This includes negative practice contrasting "new" and "old" voice patterns, conversational generalisation tasks, dyad conversations, story-building games, and real-world role plays. 4. Homework planning: Participants are given a set of tasks and asked to complete tracking logs. 5. Post-session reflections: Participants may optionally provide brief written feedback on the session. Location of activities All group sessions will take place in NHS outpatient clinic rooms at each site. No home visits are required. Specialist baseline and outcome measurements will take place at UCLH. Timetable Months 1 to 2: Train clinicians and open sites Months 2 to 4: Recruitment Months 4 to 7: Baseline assessments, delivery of six-week intervention blocks at each site, post-intervention assessments, and exit interviews Months 8 to 9: Analysis, integration of mixed-methods data, and reporting No interim analyses are planned beyond routine monitoring of recruitment, attendance, and adverse events. Behavioural The datasets generated during and/or analysed during the current study are/will be available upon request from the Chief Investigator (Brian Saccente-Kennedy, brian.saccente-kennedy@nhs.net) upon reasonable request following publication of the primary study results. Data will be retained and available for up to 10 years after study completion. Shared data may include anonymised feasibility, intervention, patient-reported, voice quality, and respiratory outcome data. Access will be considered for researchers conducting scientifically and ethically appropriate research, subject to any necessary ethical approvals and a data-sharing agreement. Participants will provide consent for sharing anonymised research data. Direct identifiers will be removed prior to sharing, and identifiable materials such as voice recordings and laryngeal imaging data will not routinely be shared. Requests will be reviewed in accordance with UK GDPR, NHS information governance requirements, and sponsor policies. Available on request d892e07d-7743-440f-912c-db008527949c 2c80c8d2-df0c-450e-a81d-32a06f89190a ae22e5ca-8b58-490a-a7d4-d00f8a600126 Yes Brian Saccente-Kennedy https://orcid.org/0000-0002-2419-3922 Principal investigator Scientific Public

Speech and Language Therapy (ENT), Royal National ENT and Eastman Dental Hospitals, Ground Floor North, 250 Euston Road

London United Kingdom NW1 2PG +44 20 3456 5180 brian.saccente-kennedy@nhs.net Public University College London Hospitals NHS Foundation Trust Hospital/treatment centre https://ror.org/042fqyp44 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 17340368 true CHAPAS-5: an adaptive platform trial for evaluation of novel treatment regimens in children and adolescents with HIV in Africa CHAPAS-5 The primary objective of CHAPAS-5 is to identify and rank the most effective antiretroviral therapy (ART) regimens for children and adolescents living with HIV, both for those starting treatment for the first time and those requiring a treatment change after failure of dolutegravir (DTG)-based therapy. Effectiveness will be assessed by the proportion of participants who are alive and have achieved viral suppression (HIV viral load <400 copies/ml) at 48 weeks. Secondary objectives include comparing two-drug versus three-drug DTG-based regimens, evaluating DTG-based versus darunavir/ritonavir (DRV/r)-based strategies after treatment failure, comparing abacavir/lamivudine with tenofovir alafenamide/emtricitabine backbones, and assessing safety, acceptability, quality of life, and cost-effectiveness of the different treatment approaches. Background and study aims This is an international research study aiming to identify the best HIV treatment options for children and adolescents living with HIV in Africa. HIV is treated with antiretroviral therapy (ART), which must be taken for life to keep the virus under control and maintain good health. Although adults living with HIV have several treatment options available, children and adolescents have fewer alternatives if their treatment causes side effects or stops working. This study will compare different HIV treatment combinations to find out which treatments work best, are safest, are easiest to take, and provide the greatest benefits for children and young people living with HIV. Who can participate? Children and adolescents may be able to participate if they: 1. Are aged at least 4 weeks and under 15 years 2. Weigh between 3 and 30 kg 3. Are starting HIV treatment for the first time or are already receiving HIV treatment but their HIV is not well controlled 4. Have at least two treatment options available within the study that their doctor considers suitable for them Participants will be recruited from Uganda, Zimbabwe, and Mozambique What does the study involve? Participants will be randomly assigned to receive one of several HIV treatment options that are considered appropriate for them by their doctor. During the study, researchers will monitor: 1. How well HIV is controlled using viral load blood tests 2. Side effects and safety of treatment 3. How well participants are able to take their medication 4. How easy and acceptable the treatment is to take 5. Mental health and quality of life 6. The costs and cost-effectiveness of different treatment options Participants will attend study visits and have routine assessments, including blood tests. They will be followed for at least 48 weeks after joining the study. What are the possible benefits and risks of participating? Possible benefits: 1. Participants may receive HIV treatments that are effective and appropriate for their needs. 2. Participants will receive regular health monitoring throughout the study. 3. Information gained from the study may help improve HIV treatment options for children and adolescents in the future. Possible risks: 1. All HIV medicines can cause side effects, although not everyone experiences them. 2. Blood tests and study procedures may cause temporary discomfort. 3. A participant's assigned treatment may not work as well for them as expected. 4. Participants may need additional tests or clinic visits as part of the study. The study team will closely monitor participants for any side effects or health concerns throughout the trial. Where is the study run from? The study is being conducted in Uganda, Zimbabwe, and Mozambique. It is organised by an international collaboration of researchers from the United Kingdom, Uganda, Mozambique, Zimbabwe, Italy, and the Netherlands. When is the study starting and how long is it expected to run for? November 2026 to December 2029 Who is funding the study? The European & Developing Countries Clinical Trials Partnership (EDCTP) Who is the main contact? The Trial Management Team at University College London’s Innovative Clinical Trials Unit, mrcctu.chapas5@ucl.ac.uk HIV viral suppression plasma HIV viral load testing, defined as being alive and having an HIV viral load <400 copies/ml, week 48 (a repeat viral load result will be used if the initial viral load is ≥400 copies/ml) 1. HIV viral suppression measured using plasma HIV viral load testing, defined as being alive and having an HIV viral load <1000 copies/ml at week 48 (a repeat viral load result will be used if the initial viral load is ≥1000 copies/ml) 2. Cross-sectional HIV viraemia measured using plasma HIV viral load testing, defined as the proportion of participants with HIV viral load ≥50 copies/ml, ≥400 copies/ml, and ≥1000 copies/ml at week 48 (using the viral load measurement closest to the scheduled week 48 visit) 3. Emergent HIV drug resistance measured using HIV drug resistance testing at week 48 4. Serious adverse events, severe adverse events, and antiretroviral treatment (ART)-modifying events measured using adverse event reporting, assessed from baseline to week 48 5. New or recurrent WHO stage 3 or 4 clinical events or death, measured using adverse event reporting and study records, assessed from baseline to week 48 6. Change in CD4 count and CD4 percentage measured using CD4 cell count and CD4 percentage testing at baseline and week 48 7. Change in weight and BMI-for-age measured using weight and height measurements to calculate BMI-for-age at baseline and week 48 Ethics approval required UCL Research ethics committee

UCL Research Ethics Team Research and Innovation Services University College London Gower Street

London United Kingdom WC1E 6BT 4808 10.1186/ISRCTN17340368 Interventional Randomized controlled trial Open (masking not used) Active Pragmatic open-label adaptive platform trial using the PRACTical design Health services research Treatment Not applicable 2029-12-30T00:00:00.000Z Mozambique Uganda Zimbabwe false 1. Aged ≥4 weeks to <15 years* with confirmed HIV infection 2. Weight ≥3 kg and <30 kg* 3. Written informed consent obtained (and assent if applicable) 4. Willing to adhere to a minimum of 48 weeks' follow-up *Upper limits of 15 years and 30 kg are for initial treatment options and may be amended when further treatment options are introduced (through a protocol amendment) If antiretroviral therapy (ART)-naive: 1. Planning to start first-line ART 2. Virologically unsuppressed with viral load (VL) ≥400 copies/ml at screening If ART-experienced: 1. ART-experienced and on DTG-based ART and have been on DTG-based ART for at least 6 months prior to screening 2. Virologically unsuppressed for at least 3 months, demonstrated by two consecutive VLs ≥400 copies/ml in the last year; the second VL must be at screening 3. Received adherence counselling as per standard practice prior to screening Mixed 4 Weeks 15 Years All 800 0 1. Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR both ALT ≥3 x ULN and bilirubin ≥2 x ULN at screening** 2. Severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) 3. Severe renal impairment, defined as creatinine clearance <30 mL/min/1.73 m², at screening** 4. Severe life-threatening illness (not expected to survive beyond two weeks) as determined by the investigator's clinical judgement 5. Eligible for less than two permitted treatment options based on tables 3 (ART-naive participants) and 4 (ART-experienced participants) 6. Concurrent participation in another clinical trial of an investigational medicinal product (IMP), medical device or other intervention 2026-11-30T00:00:00.000Z 2028-06-30T00:00:00.000Z Human immunodeficiency virus (HIV) Infections and Infestations Current interventions as of 09/09/2026: CHAPAS-5 uses a novel design called the Personalized Randomized Controlled Trial (PRACTical) design. This means that each participant will be randomly allocated to receive a treatment from a list that contains only the treatment options that are appropriate for them. Treatment will be given daily for the duration of the trial. Drug doses would be weight band-based as per WHO recommendations. In nested pharmacokinetic substudies we will be evaluating an expanded use of adult formulations. Each participant will be followed up for at least 48 weeks; the trial will end when the last participant to be randomized reaches week 48. Arm 1: ART naïve and ART experienced participants: dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) Arm 2: ART naïve and ART experienced participants: dolutegravir/tenofovir alafenamide/emtricitabine (DTG/TAF/FTC Arm 3: ART naïve participants: dolutegravir/lamivudine (DTG/3TC) Arm 4: ART experienced participants: darunavir/ritonavir (DRV/r) + tenofovir alafenamide/emtricitabine (TAF/FTC) Arm 5: ART experienced participants: darunavir/ritonavir (DRV/r) + abacavir/lamivudine (ABC/3TC) _____ Previous interventions: CHAPAS-5 uses a novel design called the Personalized Randomized Controlled Trial (PRACTical) design. This means that each participant will be randomly allocated to receive a treatment from a list that contains only the treatment options that are appropriate for them. Treatment will be given daily for the duration of the trial. Drug doses would be weight band-based as per WHO recommendations. In nested pharmacokinetic substudies we will be evaluating an expanded use of adult formulations. Each participant will be followed up for at least 48 weeks; the trial will end when the last participant to be randomized reaches week 48. Arm 1: ART naïve and ART experienced participants: dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) Arm 2: ART naïve and ART experienced participants: dolutegravir/tenofovir alafenamide/emtricitabine (DTG/TAF/FTC) or bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) Arm 3: ART naïve participants: dolutegravir/lamivudine (DTG/3TC) Arm 4: ART experienced participants: darunavir/ritonavir (DRV/r) + tenofovir alafenamide/emtricitabine (TAF/FTC) Arm 5: ART experienced participants: darunavir/ritonavir (DRV/r) + abacavir/lamivudine (ABC/3TC) Drug Phase III Dolutegravir, abacavir, lamivudine, tenofovir, emtricitabine, darunavir, ritonavir Not expected to be made available 4573ad33-c824-4332-b81d-a646bb1f483f 6f8671ef-fb50-4a88-b711-a3d9fee8c349 f81d8110-4810-426e-a64c-6a498f24bd84 22aaa762-526a-4e61-911a-859efbe5c317 No Anna Turkova Principal investigator

UCL Innovative Clinical Trials Unit Institute of Clinical Trials & Methodology 90 High Holborn

London United Kingdom WC1V 6LJ +44 (0)20 7670 4658 a.turkova@ucl.ac.uk Public Ellen Owen-Powell Public Scientific

UCL Innovative Clinical Trials Unit Institute of Clinical Trials & Methodology 90 High Holborn 2nd Floor

London United Kingdom WC1V 6LJ +44 (0)20 7670 4619 mrcctu.chapas5@ucl.ac.uk Public University College London https://ror.org/02jx3x895 Non-commercial European and Developing Countries Clinical Trials Partnership http://dx.doi.org/10.13039/501100001713 15002450 true Effects of a computerised affective training intervention for social interactions, compared with an identical-appearing sham control, on momentary anxiety in young people with elevated social anxiety symptoms: a parallel-group, double-blind, randomised controlled superiority trial Social Training of Affective Responses (STAR) To evaluate the impact of the Social Training of Affective Response (STAR) intervention, a psychological task in the form of a video game which emulates social interactions and aims to modify individuals' expectations about feared social situations, on momentary affect in young people with social anxiety. The STAR intervention will be compared to an active control which looks identical in all respects to the STAR but provides random feedback that averages to 50%. The impact of the STAR intervention will be determined as the improvement it produces on momentary anxiety compared to a sham control. Background and study aims Some young people feel very anxious in social situations and may expect other people to judge them negatively. This study is testing a new computer-based psychological training task called Social Training of Affective Responses (STAR). The task is designed like a video game and aims to help people develop more positive expectations during social interactions. Researchers want to find out whether STAR can reduce anxiety in young people who have higher levels of social anxiety symptoms. The study will compare STAR with a similar version of the task that looks the same but gives neutral feedback. The researchers will measure how the tasks affect participants’ anxiety, mood and ability to cope with negative feedback. Who can participate? People can take part if they: -Are aged 18 to 25 years -Have elevated symptoms of social anxiety -Have access to a computer with a webcam and an internet connection -Are currently living in the UK or the USA -Have sufficient English language skills to complete the questionnaires and tasks What does the study involve? Participants will take part in a single online session lasting about 1 hour, and no longer than 90 minutes First, participants will complete some assessments. They will then be randomly assigned to one of two groups. One group will complete the STAR task, while the other group will complete a similar comparison task. During the task, participants will interact with virtual people on a computer. They will be asked to predict how positively a virtual person will respond to them, answer questions about themselves while being recorded by their webcam for 15 seconds, and then receive feedback from the virtual person. Participants will also report their current mood and anxiety throughout the task. After a short break, all participants will complete a final section of the task that includes negative feedback followed by some positive feedback. This allows researchers to study how people respond to challenging social situations. What are the possible benefits and risks of participating? Participants may benefit from taking part if the training helps them feel less anxious during social situations. However, this cannot be guaranteed. Some participants may find parts of the task uncomfortable because they involve receiving feedback from virtual people, including negative feedback during the final part of the study. This could temporarily increase feelings of anxiety or discomfort. Where is the study run from? The study is run from University College London (UCL) in London, United Kingdom. When is the study starting and how long is it expected to run for? October 2026 to May 2028. Who is funding the study? Wellcome Trust (UK). Who is the main contact? Professor Argyris Stringaris a.stringaris@ucl.ac.uk Momentary Anxiety self-report (5-trial average) the end of the main intervention (end of block 2) Momentary Mood self-report (5-trial average) the end of the main intervention (end of block 2) Momentary Anxiety self-report (5-trial average) the end of the challenge block Momentary Mood self-report (5-trial average) the end of the challenge block Ethics approval required UCL Research Ethics Committee

Academic Services, UCL 1-19 Torrington Place (9th Floor)

London United Kingdom WC1E 7HB 24867/001 10.1186/ISRCTN15002450 Interventional Randomized controlled trial Blinded (masking used) Active Parallel Treatment Not applicable 2028-05-31T00:00:00.000Z United States of America true 1. Elevated symptoms of social anxiety as identified using a threshold of 19 the Social Phobia Inventory (SPIN) 2. Age between 18 and 25 (inclusive) 3. Access to a computer with a webcam and internet connection 4. Residence/Current location in the UK or US 5. For online recruitment sites like prolific we will: 5.1. Include a prolific approval rate of 95% as an inclusion criterion. This refers to the percentage participant’s previous prolific jobs that have been approved 5.2. Require participants to have previously completed at least 10 jobs on prolific 5.3. Include 2 attention checks. If participants fail both, they are excluded from the study Adult 18 Years 25 Years All 578 0 1. Don’t speak sufficient English to complete questionnaires and engage in the English language-based task 1.1. For online participants, this will be achieved by exclusively inviting participants from English speaking countries, specifically US and UK, who have indicated they are fluent in English 1.2. For local community participants, we will be recruiting through UCL which is an English speaking institution 2. Have sensory or other deficits that preclude them from processing the computerized tasks, confirmed by the participant during screening 3. Have over 50% of trials that have a reaction time of under 200 ms, checked during data cleaning 2026-10-01T00:00:00.000Z 2028-01-01T00:00:00.000Z Momentary anxiety in youth at risk for social anxiety Mental and Behavioural Disorders Current interventions as of 05/10/2026: Both the active and control tasks are Internet-delivered, using an online platform to present the participants with a sequence of social interactions and instructions. Preview versions of both tasks will be made publicly available to facilitate reproducibility. Both tasks are designed to be as closely matched as possible in terms of length (text to read) and interactivity (format, frequency, and amount of user-required input). ACTIVE ARM The intervention is inspired by the success of cognitive therapy for social anxiety, leading to a reduction of both anxiety and depressive symptoms in those patients. It is predicated on the idea that positive social surprises are the mechanism that leads to this improvement: positive social surprises are outcomes in a social situation that are better than one expects. Our intervention seeks to emulate such social situations to test this hypothesis and its usefulness for patients. Participants will be sat in front of a computer and will interact with three virtual players across three blocks during the task. On each trial, they will first rate their momentary mood and anxiety and then their expectation of how positively they believe the virtual player will rate them on that trial. Next, they will respond to a self-referential question while being video recorded for 15 seconds. Afterward, they will receive feedback from the virtual player. Importantly, the feedback will gradually change across blocks: for the two ‘main’ blocks the feedback given by the virtual player will improve throughout the block, mirroring a common real-world social dynamic, whereby social reward increases the longer one remains in an interaction (e.g. meeting a stranger who initially feels neutral but becomes progressively more engaged over time). ACTIVE CONTROL ARM The active control arm will be identical in all respects to the intervention except the feedback in the two ‘main’ blocks will be overall neutral. Specifically, feedback will be fluctuating around a mean of 50%. BOTH ARMS Following a short break, during which participants complete a brief filler task (the Speed of Comprehension Test, 1–2 minutes), both groups will complete a third 'challenge' block. In this block participants will interact with a third virtual player and receive a sequence of negative feedback. This block serves the purpose of testing affective resilience to negative feedback following the main blocks of the intervention. The third block will end with 5 trials of positive feedback. All procedures will take place over a single session (approximately 1 hour in duration). The primary analysis will be performed after the final participant has completed their final assessment (primary endpoint), no later than 90 minutes after study entry. Participants will first be stratified based on their SPIN (Social Phobia Inventory) scores prior to randomisation, with strata defined as: moderate social anxiety (SPIN 19-30), severe social anxiety (SPIN 31-40), and very severe social anxiety (SPIN >40). Within each stratum, participants will be randomly assigned to the intervention or control condition using a computer-generated randomisation procedure implemented in JavaScript: for each participant, a random number between 0 and 1 will be generated, with allocation to condition determined by whether the number falls above or below 0.5. This ensures random allocation within each severity stratum and controls for baseline differences in social anxiety severity across conditions. Allocation happens algorithmically via a script that runs automatically on the study platform. The two conditions are identical in all respects - including graphics, design of social interactions, and timing/phrasing of prompts and feedback - except for the social feedback participants receive, which ensures participant blinding to condition. The data management group will provide the investigator team with data in which the group variable is coded using random letters (e.g., D, G), ensuring analyst blindness. All study personnel who can be blinded to the study aims/hypotheses and group allocation will be blinded; the study statistician will also be blind to group allocation and will receive only the reduced dataset required for analysis. Once statistical analyses are completed, and before unblinding, different versions of the abstract will be prepared reaching different conclusions (e.g., intervention A superior to B, or vice versa), to preserve blinding during interpretation. Given the brief, low-risk nature of the intervention, a procedure for emergency unblinding is not required. Previous interventions: Both the active and control tasks are Internet-delivered, using an online platform to present the participants with a sequence of social interactions and instructions. Preview versions of both tasks will be made publicly available to facilitate reproducibility. Both tasks are designed to be as closely matched as possible in terms of length (text to read) and interactivity (format, frequency, and amount of user-required input). ACTIVE ARM The intervention is inspired by the success of cognitive therapy for social anxiety, leading to a reduction of both anxiety and depressive symptoms in those patients. It is predicated on the idea that positive social surprises are the mechanism that leads to this improvement: positive social surprises are outcomes in a social situation that are better than one expects. Our intervention seeks to emulate such social situations to test this hypothesis and its usefulness for patients. Participants will be sat in front of a computer and will interact with three virtual players across three blocks during the task. On each trial, they will first rate their expectation of how positively they believe the virtual player will rate them. Next, they will respond to a self-referential question while being video recorded for 15 seconds. Afterward, they will receive feedback from the virtual player and then report their current mood and anxiety. Importantly, the feedback will gradually change across blocks: for the two ‘main’ blocks the feedback given by the virtual player will improve throughout the block, mirroring a common real-world social dynamic, whereby social reward increases the longer one remains in an interaction (e.g. meeting a stranger who initially feels neutral but becomes progressively more engaged over time). ACTIVE CONTROL ARM The active control arm will be identical in all respects to the intervention except the feedback in the two ‘main’ blocks will be overall neutral. Specifically, feedback will be fluctuating around a mean of 50%. BOTH ARMS Following a short break, during which participants complete a brief filler task (the Speed of Comprehension Test, 1–2 minutes), both groups will complete a third 'challenge' block. In this block participants will interact with a third virtual player and receive a sequence of negative feedback. This block serves the purpose of testing affective resilience to negative feedback following the main blocks of the intervention. The third block will end with 5 trials of positive feedback. All procedures will take place over a single session (approximately 1 hour in duration). The primary analysis will be performed after the final participant has completed their final assessment (primary endpoint), no later than 90 minutes after study entry. Participants will first be stratified based on their SPIN (Social Phobia Inventory) scores prior to randomisation, with strata defined as: moderate social anxiety (SPIN 19-30), severe social anxiety (SPIN 31-40), and very severe social anxiety (SPIN >40). Within each stratum, participants will be randomly assigned to the intervention or control condition using a computer-generated randomisation procedure implemented in JavaScript: for each participant, a random number between 0 and 1 will be generated, with allocation to condition determined by whether the number falls above or below 0.5. This ensures random allocation within each severity stratum and controls for baseline differences in social anxiety severity across conditions. Allocation happens algorithmically via a script that runs automatically on the study platform. The two conditions are identical in all respects - including graphics, design of social interactions, and timing/phrasing of prompts and feedback - except for the social feedback participants receive, which ensures participant blinding to condition. The data management group will provide the investigator team with data in which the group variable is coded using random letters (e.g., D, G), ensuring analyst blindness. All study personnel who can be blinded to the study aims/hypotheses and group allocation will be blinded; the study statistician will also be blind to group allocation and will receive only the reduced dataset required for analysis. Once statistical analyses are completed, and before unblinding, different versions of the abstract will be prepared reaching different conclusions (e.g., intervention A superior to B, or vice versa), to preserve blinding during interpretation. Given the brief, low-risk nature of the intervention, a procedure for emergency unblinding is not required. Behavioural The datasets generated during and/or analysed during the current study will be stored in a publicly available repository (github) Stored in publicly available repository Protocol

897e98a0-f3cd-40b6-921e-8a97a4e4c007 6ac3bd57-52bc-4de1-b31b-1eaab37d8e1a bb4ac96c-1268-4859-9518-4eb75474f3e5 Yes Protocol file 49976 Protocol v1.0 20Nov2025.pdf 6fac3723-e6af-4888-80f2-5838b99e0e6a true application/pdf 375965 69dfacff7b1a77e65f502b12954a2b77 Statistical Analysis Plan 49976 SAP v0.23 08Jun2026.pdf 18c558b3-eed9-4905-b4c0-93b33a843d42 true application/pdf 265362 d99ad8a3cb9e78b98aa42216b7e58c8c Argyris Stringaris https://orcid.org/0000-0002-6264-8377 Principal investigator Public Scientific

1-19, Torrington Pl, University College London

London United Kingdom WC1E 7HB +44 (0) 7514 851520 a.stringaris@ucl.ac.uk Public University College London Non-commercial Wellcome Trust http://dx.doi.org/10.13039/100010269 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