12925425 true Under stress: Why women of black African-Caribbean heritage are at elevated risk of stroke Primary hypothesis 1: There will be a difference in the increase in large and small vessel pulsatility during mental stress in normotensive Black African-Caribbean women versus normotensive White European women. Primary hypothesis 2: There will be a difference in the increase in large and small vessel pulsatility during mental stress in hypertensive Black African-Caribbean women versus hypertensive White European women Background and study aims Black African and Caribbean women are three times more likely to experience stroke and are more likely to have a stroke at a young age. What causes this is unknown, but stress appears to play an important role. High levels of daily stress may increase the risk of stroke in Black African Caribbean women. This is because Black women often have bigger spikes in blood pressure during stress. These large and frequent blood pressure spikes may cause damage to the brain over time. Therefore, we want to understand how the brain responds to these spikes in blood pressure and explore whether the blood vessels in the brain are less able to protect against these blood pressure spikes in Black African Caribbean women. Who can participate? Women of Black African and Black Caribbean heritage and women of White European heritage, between 18 and 75 years old. What does the study involve? Taking part involves two visits: one visit to the Clinical Research Facility in Bristol, which will take about 3 hours and one visit to the Cardiff University Brain Imaging Research Centre in Cardiff, which will take around 2 hours. Visit 1: Screening tests to ensure eligibility. Completion of questionnaires assessing social determinants of health and health behaviours including physical activity levels, diet, sleep quality, experience of discrimination, and stress levels. Non-invasive assessment of blood pressure and leg blood flow responses to a math task. Venous blood sample to determine stress hormone levels at rest and during a math task. Visit 2: Non-invasive assessment of large artery stiffness. Participants will then undergo a brain MRI. Scans will be taken at rest, during a mental math task and during occlusion of the forearm with a blood pressure cuff pumped to a high pressure (i.e., metaboreflex test). What are the possible benefits and risks of participating? This study is testing the impact of stress on blood pressure and brain function. Taking part will help us understand why high levels of stress increase the risk of stroke in Black women. This can also help identify preventative treatments. You will get a full blood pressure screen, which may be of some benefit to you from a health check-up perspective. You will also get information on your cholesterol levels and diabetes risk This study involves minimal risks Venous blood sample and cannulation: mild discomfort during venepuncture/cannulation and mild swelling or bruising at the site. Monitoring heart rate, blood pressure and breathing: mild discomfort from the inflation of the blood pressure cuff around the finger. Mental math test: the task may cause some stress, however, this will stop when the task stops. Metaboreflex test: mild arm discomfort with the blood pressure cuff being inflated to stop blood from leaving your arm. Brain MRI: MRI is a safe, non-invasive and painless procedure. However, some people find being inside the scanner claustrophobic. Some people may experience discomfort from lying down in the scanner for 1 hour. Where is the study run from? University of Bristol (UK) When is the study starting and how long is it expected to run for? April 2024 to January 2028 Who is funding the study? British Heart Foundation (UK) Who is the main contact? Dr Lydia Simpson, Lydia.simpson@bristol.ac.uk Cerebral pulsatility index measured from MRI at rest and during Paced Auditory Serial Addition Task (PASAT) 1. White matter hyperintensities measured using MRI at rest 2. Blood-brain barrier integrity measured using MRI at rest 3. Grey matter perfusion measured using MRI at rest 4. Cardiovascular hemodynamics measured continuously during a 10-minute resting period and during the PASAT: 4.1. Heart rate measured continuously via ECG 4.2. Beat-to-beat blood pressure measured via finger photoplethysmography 4.3. Continuous femoral blood flow measured via Doppler ultrasound 5. Stress hormones (cortisol and catecholamines) during mental stress measured from venous blood samples taken at rest and during the PASAT 6. Systemic arterial stiffness measured using carotid-femoral pulse wave velocity at rest 7. Cerebral arterial stiffness measured from MRI at rest Ethics approval required North East - Newcastle & North Tyneside 2 Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/NE/0209 10.1186/ISRCTN12925425 347113 CPMS: 64223, Sponsor Ref: 2024 - 4520 347113 64223 Sponsor Ref: 2024 - 4520 Observational cross-sectional study Observational Cross sectional study Other 2028-01-01T00:00:00.000Z United Kingdom England Wales NIHR Bristol Clinical Research Facility

60 St Michael's Hill

Bristol United Kingdom BS2 8DX CRF34@2.16.840.1.113883.2.1.3.8.1.2 Cardiff University Brain Imaging Centre

Maindy Road

Cardiff United Kingdom CF24 4HQ Healthy volunteer Patient All participants: 1. Female 2. 18-75 years of age 3. Non-obese (BMI <35 kg/m2) Normotensive participants: 1. Office BP < 140/90 mmHg and daytime ambulatory BP <135/85 mmHg 2. No medications except oral contraceptives Hypertensive participants: 1. Office BP > 140/90 mmHg and daytime ambulatory BP > 135/85 mmHg or diagnosis of hypertension 2. No medications except treatment for hypertension and/or oral contraceptives Adult 18 Years 75 Years Female 64 All participants: 1. Body mass index ≥35 kg/m2 2. Major illness e.g. cancer, inflammatory disease (including vasculitis) or receiving palliative care 3. Medical history of respiratory, cardiovascular (excluding hypertension), cerebrovascular, metabolic, renal or endocrine disorders (i.e. severe cardiac electrical conduction abnormalities, chronic heart failure, Chronic Obstructive Pulmonary disease, diabetes, polycystic ovary syndrome) 4. Inherited disorders e.g., sickle cell anaemia 5. Pregnancy/breastfeeding women 6. Taking nitrate, steroid, anti-coagulant or immunosuppressant medication or medication as part of a clinical trial 7. Diagnosed cardiovascular (including arrhythmia), respiratory (including asthma), renal or ophthalmic disease 8. Congenital or acquired neurological conditions (including dementia), language disorders, repeated or chronic pain conditions (excluding menstrual pain and minor sporadic headaches) 9. Diabetes or HbA1c >6.5% 10. Symptoms of febrile illness within two weeks of participation 11. Excessive alcohol consumption (exceeding 28 units/week) or intravenous drug use 12. Needle phobia 13. History of panic attacks 14. Inability to understand instructions given in English 15. Current smoker 16. Pacemaker, implantable cardiac defibrillator, cerebral metallic clips or other implanted metallic devices/structures 17. Unable to tolerate scanner or history of claustrophobia 18. Learning disability or significant hearing and/or visual impairment, which may affect participants ability to communicate from within the MRI scanner 19. Inability to understand English Normotensive: 1. Women with a history of hypertension, including hypertension in pregnancy Hypertensive participants: 2. Secondary causes of hypertension 2025-02-18T00:00:00.000Z 2027-10-01T00:00:00.000Z Hypertension Circulatory System This study will be a cross-sectional study of four groups: normotensive Black African and Black Caribbean women, normotensive White European women, hypertensive Black African and Black Caribbean women and hypertensive White European women. Two study visits: Visit 1: Consent and screening visit and determination of hemodynamic and sympathetic responses to mental stress. Visit 1 will be undertaken at the NIHR Clinical Research Facility, Bristol. First, consent will be obtained, and participants' eligibility will be determined. Following screening, several questionnaires will be completed to assess social determinants of health and health behaviours. Venous blood samples will be taken at rest to measure catecholamines and cortisol. BP, heart rate, respiratory activity and vascular ultrasound will be measured at rest and during a mental arithmetic task, used to induce mental stress. A second blood sample will be taken during the mental arithmetic task to determine changes in catecholamines and cortisol, from rest. Study visit 2: MRI visit and determination of cerebrovascular responses to mental stress. Visit 2 will be undertaken at Cardiff University Brain Research Imaging Centre (CUBRIC). Participants will be familiarised using a mock MRI scanner. Resting pulse wave velocity will be assessed. BP, peripheral oxygen saturation, respiratory activity, and end-tidal partial pressure of CO2 and O2 will be measured, and MRI imaging will be completed at rest and during 1) mental arithmetic task and 2) during metaboreflex testing. Other The datasets generated and/or analysed during the current study will be available upon request from Dr Lydia Simpson (Lydia.simpson@bristol.ac.uk) Available on request bcb1d7fe-5be0-4292-93af-3e67bd08d1d8 d041b078-9a2a-4344-a8b6-dd91c4e97648 ce82fe3b-8c6c-4174-92ee-2e83132aff8a Yes Lydia Simpson Public Scientific Principal investigator

Biomedical Sciences Building University of Bristol

Bristol United Kingdom BS81TD +44 (0)7795123830 Lydia.simpson@bristol.ac.uk Public British Heart Foundation Charity https://ror.org/02wdwnk04 Non-commercial British Heart Foundation http://dx.doi.org/10.13039/501100000274 11023869 true The effects of Piano Instruction for Adult Novices as Online Cognitive intervention (PIANO-Cog) on executive function, fluid intelligence and white and grey matter microstructure compared to passive control in healthy older adults PIANO-Cog Our primary hypotheses are: 1. PIANO-Cog will be a feasible online cognitive training intervention for healthy non-musicians over the age of 50 years old. 2. A future fully-powered RCT into the effects of 8-weeks of home-based PIANO-Cog training compared to no-training control will be feasible. Our secondary hypotheses are that, in healthy non-musicians (>50 years), 8 weeks of piano training will: 1. Lead to improvements in processing speed, response inhibition and attention switching as measured by digit-symbol substitution test, a Stroop test, Go/No-go test and verbal fluency category switching tasks 2. Lead to grey and white matter microstructural changes in auditory, motor and somatosensory networks measured using DTI and metrics from the biophysical models, NODDI and SANDI. Specifically, we expect to see an increase in soma density and soma size metrics from SANDI model and increased orientation dispersion and intracellular density metrics from the NODDI model following piano training compared to the control group. 3. Underlying microstructural changes will be associated with changes in processing speed (digit-symbol task) and EF (N-back, Stroop and Go/No-go tasks). Background and study aims As we age, our cognitive abilities can decline. Research suggests that activities combining sensory and motor skills, like musical training, might help improve cognitive functions in older adults. This study aims to test a self-guided piano training program called PIANO-Cog, which participants can do at home. The goal is to see if this program is acceptable to participants and if a larger study would be feasible. Who can participate? Cognitively healthy volunteers over the age of 50, with little-to-no musical training, can take part in this study. What does the study involve? Participants will undergo 2 hours of cognitive testing and a 30-minute MRI scan before and after an 8-week intervention period. They will be randomly assigned to either the piano training group or a control group. The piano group will receive a 30-minute training video each week and are asked to practice for 30 minutes, 5 days a week. The control group will continue their usual activities and avoid any musical or cognitive training during the study. What are the possible benefits and risks of participating? Participants may not directly benefit from the study. Those in the piano training group will receive a keyboard for 8 weeks, but it must be returned after the study. Control group participants will get the piano training videos after the study ends. There are small risks associated with MRI scanning, such as discomfort in confined spaces and the need to remain still. Cognitive testing can be tiring, but breaks will be provided as needed. Where is the study run from? Cardiff University Brain Research Imaging Centre (CUBRIC), Maindy Road, Cardiff (UK) When is the study starting and how long is it expected to run for? March 2023 to July 2025 Who is funding the study? School of Psychology, Cardiff University (UK) Who is the main contact? Fionnuala Rogers (RogersF2@cardiff.ac.uk) 1. Recruitment rate = 100 x (number of participants who provided consent / number of participants eligible) % 2. Retention rate = 100 x (number of participants who complete follow-up testing / number of participants who provided consent) 3. Adherence rate (frequency) = 100 x (number of days’ practice logged / 40 days) % 4. Adherence rate (duration) = 100 x (number of minutes practice logged / (40 days x 30 minutes average session duration = 1,200 minutes) % 5. Acceptability of the intervention is assessed using an evaluation survey consisting of 27 x 6-point Likert scale items on how participants perceived the quality, difficulty level and content of the training. Four qualitative questions are also included to ask participants for their individual feedback. 1. Processing speed measured as the number of correct responses within 90 seconds on the symbol-digit test from the WAIS-III. 2. Inhibitory control for motor responses measured as the rate of correct responses and latencies on the Go/No-go test. 3. Inhibitory control for distractor information measured as the number of correct responses and latencies on a computerised Stroop task for congruent versus incongruent trials. 4. Working memory capacity measured as the number of correct responses on the digit span task (forward and backward conditions) from the WAIS-III. 5. Updating of working memory measured as the error rates on the N-back. 6. Visual attention and attention-switching measured by completion times on the Trail-Making Task Parts A and B respectively. 7. Verbal fluency measured by the number of correct responses provided on the letter, category and category-switching subtests of the D-KEFS verbal fluency test. 8. Verbal memory measured as the total number of words recalled on the California Verbal Learning Test - II. 9. Musical abilities measured as score from the micro-PROMS which assess a participant's ability to detect changes in samples of music. 10. Piano performance measured as the number of correct notes and timing accuracy measured whilst playing 5-finger scales using a MIDI-keyboard and Reaper, compared with a reference. 11. Changes in grey matter microstructure assessed by the soma size and soma density metrics from the Soma And Neurite Density Imaging (SANDI) model which will be applied to multi-shell high angular resolution diffusion imaging data (msHARDI) collected using ultra-high gradients of the Siemens Connectom. 12. Changes in white matter microstructure assessed using the Neurite Orientation Dispersion and Density Imaging (NODDI) model which provides the isotropic signal fraction (ISOSF) as an estimate of free water, intracellular signal fraction as an estimate of axon density, and the orientation dispersion index (ODI) as an estimate of axon orientation and dispersion. Ethics approval required School of Psychology Research Ethics Committee, Cardiff University

70 Park Place

Cardiff United Kingdom CF10 3AT EC.23.05.16.6801GRA 10.1186/ISRCTN11023869 Two-arm single-blinded randomized controlled trial (pilot feasibility study) Interventional Randomised controlled trial Prevention Quality of life 2025-07-30T00:00:00.000Z United Kingdom Wales CUBRIC

Maindy Road

Cardiff Wales CF24 4HQ Healthy volunteer 1. >50 years old 2. Fluent English speakers 3. Have normal/corrected-to-normal vision and hearing 4. Have less than 4 years of formal musical or dance training 5. Are not involved in any musical activities 6. Have no neurological or psychiatric history that could affect learning (e.g., dementia, stroke or traumatic brain injury, depression requiring hospitalisation) 7. No self-reported difficulty with hand movement 8. No self-reported learning disabilities Mixed 50 Years 99 Years All 50 0 1. Impaired hearing or vision 2. Neurological diagnosis 3. Current involvement in other cognitive training or musical activities (e.g., choir singing, dance or exercise to music classes) 4. More than 4 years of formal music or dance lessons 5. Currently taking psycho-reactive medications which affect memory performance 6. Participants with MRI contra-indications (e.g., pacemakers, stents, cochlear implants, or other metal in the body such as metallic plates, screws or clips) will not be scanned, but will still be eligible for training and cognitive and motor testing 2024-08-15T00:00:00.000Z 2025-06-01T00:00:00.000Z Age-related cognitive decline and neurodegeneration. Mental and Behavioural Disorders Cognitively healthy non-musicians over 50 years will be recruited and screened for cognitive impairment and < 4 years music experience. They will be assigned to either self-guided piano training or a passive control for 8 weeks. Piano training consists of video-guided tutorials which can be carried out in participant's homes. Cognitive assessments and diffusion MRI will take place before and after the intervention period. The groups will be stratified by sex and by two age categories: 50-65 years and >65 years. Pseudo-random numbers will be used to generate randomised group allocation per stratum using R version 4.41, and implemented by the lead researcher. Neither participants nor the researcher conducting baseline testing will be informed of group allocation until after baseline testing is completed, as the algorithm determining group allocation will take place only at the end of testing. Behavioural The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. Cognitive and MRI data will be made openly available on OSF. Stored in publicly available repository 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/41402938/ (added 17/12/2025) Protocol

d7fd40f8-d488-4f8a-b227-6b7f788f8593 133c1761-b04e-45b4-b196-77e40088b78b 89aac1da-7f5c-43a3-bb69-a61101f00459 Yes Participant information sheet 46395 PIS Piano MRI Study v3 14.06.24.pdf a048a395-338f-41a0-bc11-04c3f3916ab3 true application/pdf 1512874 00c2411713294de3331f7e242ec509ed Fionnuala Rogers https://orcid.org/0000-0002-1001-7653 Public Scientific Principal investigator

CUBRIC

Cardiff United Kingdom CF24 4HQ +44 (0)29 2087 0365 RogersF2@cardiff.ac.uk Public Cardiff University University/education https://ror.org/03kk7td41 Non-commercial School of Psychology, Cardiff University http://dx.doi.org/10.13039/501100008533 11906973 true Feasibility randomised controlled pilot study of HD-DRUM - a novel motor activity (drumming) training app for people with Huntington's disease HD-DRUM The adherent use of HD-DRUM is feasible in individuals with presymptomatic/early-moderate manifest Huntington's disease (HD). Background and study aims Huntington’s Disease (HD) is an inherited disease that causes cell loss in brain regions important for learning and planning movements and doing two things at once (multitasking). HD leads to a worsening of these abilities. There is no cure for HD and there are currently no NHS services that can alter the progression of movement and thinking changes. Also, the current COVID-19 pandemic has highlighted the urgent need for support that can be accessed at home when clinic visits are not possible. This project will test a new movement and rhythm training tool that people with HD can use at home. This involves learning drumming patterns that gradually increase in difficulty. Drumming requires key abilities of concentration, planning and making movements and multi-tasking (e.g. listening and drumming). HD affects all of these abilities as they rely on brain regions impaired by the disease. The drumming tool will train these key abilities. The training is based on many studies in HD mice showing that movement symptoms can be delayed when mice have access to an enriched environment with more for them to do and think about. Movement and thinking training was also shown to help people with Alzheimer’s and Parkinson’s disease and can make brain changes including the strengthening of connections. Importantly, I found that two months of Bongo drumming improved concentration and multi-tasking abilities in people with HD and strengthened their brain connections. However, these pilot findings were just in a small number of people and need to be tested in larger groups. Further, we have since developed a digital drumming training, the HD-DRUM app, that allows people to always practise at the level that is best for them, i.e., neither too easy nor too hard. The app also allows to record training improvements, to see if people are training when they should be, and to make it available to everyone interested in using it. Who can participate? Adults over 18 years, with HD. What does the study involve? This feasibility study will test how easy it is for people who have not yet developed movement symptoms or have only mild-moderate changes to use HD-DRUM at home for three months (15 min per day, 5 days a week). Half of them (n = 25) will be using HD-DRUM while continuing their standard care and the other half (n = 25) will receive standard care only so that the two groups can be compared. Further a group of age, sex and education-matched healthy participants (n = 25) will also be using HD-DRUM for 3 months at home. Everybody will have some movement and thinking tests and brain scans at the beginning and end of the study. These tests will inform about the number of participants needed for a future bigger randomised controlled (RCT) trial for studying the effects of HD-DRUM on movement and thinking and the brain. In addition, the comparison between people with HD and healthy controls will allow us to identify any disease-related differences in thinking, movement, and the brain before and after the training. This will help us to identify who may benefit most from the training and whether patients recruit different brain regions to learn drumming patterns than healthy participants. What are the possible benefits and risks of participating? In the future, HD-DRUM may be able to provide a remotely accessible training tool to help improve movement and thinking in HD without the risk of harmful side-effects. Even a small delay in symptoms starting due to the strengthening of brain connections and function would have direct and significant benefits for the quality of life of people with HD and their families. Potential risks – Cognitive assessments and HD-DRUM training For the cognitive assessments and HD-DRUM training intervention, there are no obvious ethical or safety concerns. The proposed cognitive assessments are standard neuropsychological assessment that have been widely used in the Enroll-HD study to assess HD patients. Further we did not observe any safety issues in our pilot work on drumming training and computerised cognitive training in people with HD. However, there is a small risk associated with any psychological assessment and intervention to cause distress or harm: all study and intervention material will therefore be co-produced and reviewed by stakeholders in order to minimise risk of distress. HD-DRUM implements an adaptive training schedule that will avoid distress due to over- or underchallenge. Potential risks – MRI assessments MRI scanning is non-invasive and has no known significant adverse health effects when appropriate screening and safety measures are in place and implemented and CUBRIC Standard Operating Procedures will be followed. MRI scans involve a strong magnetic field so that participants with certain mechanical or electronic devices cannot be scanned (e.g. pacemakers, artificial heart valves, neurostimulators). All participants will therefore be carefully screened to ensure that MRI scanning will be safe for them. Rarely, someone finds the scanner too claustrophobic: all participants will be asked about this and will also be given the opportunity to lie in a mock scanner (without a magnetic field) to experience what the scanning will be like. As MRI scanning is noisy all participants will be provided with ear protection. Verbal contact will be maintained between the investigators and the participant through the use of intercom, and a call button will be given to the participant to enable them to stop the scanning procedure at any time. A few people have reported minor side effects during MRI scanning including dizziness, mild nausea, a metallic taste in the mouth, and the sensation of seeing flashing lights. These side effects, if experienced, resolve after leaving the magnet and participants will be warned at the beginning of the MRI scanning session of these rare side effects. In some circumstances, the changes in the magnetic field in the MRI scanner could make an electric current flow through some of the volunteer’s body, causing peripheral nerve stimulation, this is rare and not harmful but may be uncomfortable. If two parts of the volunteer’s body were touching (for instance legs crossed) then in very rare occasions it is possible that an induced current may cause skin heating. Volunteers are instructed to lie with arms to their sides, and legs uncrossed, which stops this from happening. It will also be explained to participants that the researchers do not have expertise in MRI diagnosis, as they are not medical doctors. Participants should not regard the research scans as medical screening procedures and if they had any health concerns, they should contact their medical practitioner in the normal way. In the unlikely event of an unexpected finding, a neurological consultant will be asked to examine the scans, and if appropriate to report back to the participants’ GP. Where is the study run from? University of Cardiff (UK) When is the study starting and how long is it expected to run for? August 2020 to April 2026 Who is funding the study? Health and Care Research Wales (UK) Who is the main contact? Dr Claudia Metzler-Baddeley metzler-baddeleyc@cardiff.ac.uk 1. Feasibility of recruitment will be assessed by recording the number of participants enrolled and consented into the study per clinic per month. 2. Retention will be measured by the number of participants who complete the study. Number and study and non-study-related reasons for drop-out will be recorded. 3. Acceptability will be measured with a semi-quantitative self-report questionnaire asking participants to rate how engaging/motivating/frustrating the training was, whether the training frequency, duration, and difficulty was appropriate, whether they perceived any beneficial/detrimental training effects, what they liked/disliked and what aspects could be improved. This information will provide feedback for any adjustments that may need to be made to HD-DRUM in preparation for a future RCT. 4. Adherence to the training will be automatically tracked with HD-DRUM by recording the frequency and duration of training sessions. 1. Computer and Paper based cognitive and motor tasks Training-induced transfer effects to untrained motor and cognitive tasks will be estimated with paper and pencil and computerised tasks to test motor and cognitive functions at baseline and follow-up study visits. These include tasks from the core-assessment protocol of the ENROLL-HD study and computerised tasks from the Psychology Experiment Building Language (PEBL) Test library. The pace of cognitive assessments will be led by the participant although it is not expected that the completion of the cognitive tasks will exceed 2 hours. The following tasks were chosen for the purpose of identifying the best clinical outcome measure for a future RCT. 1.1. Motor functions will be assessed with the Motor Score and the Diagnostic Confidence Index from the United Huntington’s Disease Rating Scale (UHDRS) and with a computerised finger tapping task from PEBL. 1.2. Everyday functioning will be assessed with the Total Functional Capacity, the Functional Assessment Scale and the Independence Scale from UHDRS. 1.3. Cognition will be assessed with the Symbol Digit Modality Test, Stroop word reading, Stroop colour naming and interference, letter and category fluency and Trail Making A & B from the core-assessment of ENROLL-HD. Executive functions of distractor suppression (Flanker task), updating (n-back), attention switching (complex span) and dual tasks will be assessed with PEBL. 2. MRI morphology and microstructure Brain morphology and microstructure of cortico-striatal-thalamic and cerebellar networks will be assessed at baseline and at 3 months follow-up to assess training-induced brain plasticity mechanisms. MRI scanning will be done on the National Microstructural Imaging Facility, a 3 Tesla MRI Siemens Connectom system with ultra-strong (300mT/m) gradients. MRI data acquisition time on the Connectom scanner will be ~60 min and optional additional scanning on the 7T Magnetom will be ~30 min: 2.1. T1-weighted anatomical images [magnetization prepared-rapid gradient echo sequence, 1x1x1 mm3 resolution, field-of-view: 256 x 256, repetition time (TR) = 2300 ms, echo time (TE)= 2 ms, TI = 857 ms, flip angle: 9] as reference images for all microstructural maps and to gain volume and cortical thickness measurements60. 2.2. Multi-shell diffusion-weighted data [2x2x2 mm³ resolution; TE/TR = 59/3000 ms; δ/Δ: 7/24 ms; b-values = 0 (14 volumes), 500 (30 directions), 1200 (30 directions), 2400 (60 directions), 4000 (60 directions), and 6000 (60 directions) s/mm²] to fit multicompartment models such as the Composite Hindered And Restricted Model of Diffusion (CHARMED)61 and the Neurite Orientation Density and Dispersion (NODDI)62 model yielding maps of the restricted signal fraction (Fr), estimating axon density, of the orientation dispersion index (ODI), estimating neurite complexity, and of the isotropic signal fraction (ISOSF), estimating free water. 2.3. Quantitative Magnetization transfer (MT)-weighted data [1.72x1.72x1.72 mm³ resolution, turbo flash sequence, turbo factor 4, non-selective excitation MT pulse duration: 15.36 ms, 11 MT-weighted volumes and 1 volume without MT-weighting, 11 Frequency offsets (Hz) and 11 flip angles (degrees): 47180 (628); 56360 (332); 12060, (628); 1000 (332);1000 (333); 2750 (628); 2770 (628); 2790 (628); 2890 (628); 1000 (628); 1000 (628)]63 to gain the macromolecular proton fraction (MPF) as an estimate of WM myelin. 2.4. An optional high-resolution T1-weighted anatomical scan [magnetization prepared-rapid gradient echo sequence, 0.7x0.7x0.7 mm³ resolution, field-of-view: 256 x 256, repetition time (TR) = 5000 ms, echo time (TE)= 2.45 ms, TI1 = 900 ms, T12 = 2750 ms; flip angle1: 5, flip angle2 = 3] at 7Tesla (gradient strength 70mT/m) on the Siemens Magnetom MRI scanner to obtain high-resolution images of the basal ganglia and cerebellum regions as well as susceptibility and R2* maps to characterise basal ganglia tissue properties of myelin and iron. Old ethics approval format Approved 06/07/2022, Wales Research Ethics Committee 2 (Castlebridge 4, 15-19 Cowbridge Road East, Health & Care Research Wales Ethics Service, Cardiff, CF11 9AB, UK; +44 (0)2922941119; Wales.REC2@nhs.wales.uk), ref: 22/WA/0147 10.1186/ISRCTN11906973 310261 310261 Two-arm feasibility randomized controlled pilot study Interventional Randomised controlled trial Other 2026-04-30T00:00:00.000Z United Kingdom England Wales Cardiff University Brain Research Imaging Centre (CUBRIC)

Maindy Road Cathays

Cardiff Wales CF24 4HQ Patient Current inclusion criteria as of 06/02/2024: Individuals over the age of 18 years with premanifest or early/moderate manifest HD as confirmed by genetic testing for the presence of the mutant huntingtin allele with a Total Functional Capacity score between 9 and 13, sufficient motor control to perform drumming and on stable medication for a minimum of four weeks prior to enrolment. Previous inclusion criteria: Individuals over the age of 18 years with premanifest or early/moderate manifest HD as confirmed by genetic testing for the presence of the mutant huntingtin allele with sufficient motor control to perform drumming and on stable medication for a minimum of four weeks prior to enrolment. They will have participated in at least two cognitive testing sessions for the ENROLL-HD registry to reduce the burden (cognitive data collected within a month prior to pilot will be used as baseline data) and practice effects of repeated testing. Mixed 18 Years 100 Years All 50 55 A history of any other neurological condition than HD and an inability to provide consent. 2023-01-01T00:00:00.000Z 2025-03-30T00:00:00.000Z Improving cognitive and motor symptoms with drumming in people with Huntington's disease Nervous System Diseases The study will take place at the Cardiff University Brain Research Imaging Centre (CUBIRC) and at participants’ homes. Half of the participants (n = 25) will be randomised to receive HD-DRUM at home while the other half (n = 25) will be a non-intervention standard medical care control. Randomisation either with REDCap tool or Minim computer software. Participants in the HD-DRUM motor activity training group will be given a tablet with the HD-DRUM drumming app and written and video instructions installed. They will be asked to use HD-DRUM five times per week for 15 min for 12 weeks. The researchers will be in weekly contact with them to see how they are progressing and to record any problems/barriers. Control participants will receive no intervention apart from their routine medical care but will have the opportunity to try HD-DRUM after study completion. They will also be contacted on a weekly basis to control for social contact with the researchers. All participants will undergo two cognitive and MRI assessments at CUBRIC, before and after the 12 weeks study period. Brain morphology and microstructure of cortico-striatal-thalamic and cerebellar networks will be assessed at baseline and at 3 months follow-up to assess training-induced brain plasticity mechanisms. Informed consent, specific to MRI scanning will be conducted prior to each scan. The MRI scanning procedure will be carefully explained and discussed with the participant and the participant will have the opportunity to experience lying in a simulated MRI scanner (‘mock scanner’), if they feel this may be helpful. Research visits to conduct MRI scans will be arranged prior to beginning the HD-DRUM training intervention and again after the 12 weeks intervention for both intervention and control groups, in order to address the mechanism. Prior to scanning, all participants will be screened for contradictions to MRI and the procedure will be carefully explained to them. An MRI scan will then be conducted by a fully trained MR Operator at CUBRIC. MRI data acquisition will take about 60 min. MRI scanning will be done on the National Microstructural Imaging Facility, a 3 Tesla MRI Siemens Connectom system with ultra-strong (300mT/m) gradients that is only available in CUBRIC within the UK. Ultra-strong gradients allow the acquisition of diffusion-weighted data with high b-values for the estimation of intracellular diffusion properties. These were shown to be more sensitive to WM microstructure than standard diffusion tensor imaging indices. In addition, patients will be offered an optional high-resolution anatomical scan on the 7 Tesla MRI Siemens Magnetom system to gain high-resolution images of the basal ganglia and the cerebellum. All MRI protocols have been piloted in individuals with HD and healthy participants and were well-tolerated. Our previous research has identified microstructural differences in HD patients compared with healthy controls. Importantly, we found drumming training-induced increases in an estimate of white matter myelin. MRI data acquisition time on the Connectom scanner will be ~60 min and optional additional scanning on the 7T Magnetom will be ~30 min. Behavioural Data will be stored and managed on RedCap. Anonymised data can be obtained on request from the principal investigator Dr Claudia Metzler-Baddeley (metzler-baddeleyc@cardiff.ac.uk). Available on request 2024 Protocol article in https://pubmed.ncbi.nlm.nih.gov/39089721/ (added 02/08/2024) 2023 Other publications in https://pubmed.ncbi.nlm.nih.gov/37801351/ Intervention design (added 06/02/2024) Protocol

Intervention design

7d300966-d53c-449f-a68f-f587bf749228 70c003ac-14d7-4c1b-8163-7bdfc8ef47bc 64daee09-c1f5-431c-bbf0-cf70cc61c076 Yes Statistical Analysis Plan ISRCTN11906973_SAP_V1.1_03Feb2025.pdf 24d200dd-6c61-460c-a9d3-d8ecb9055aa5 true application/pdf 215112 4fc460024e336d699e69cb42e402471e Claudia Metzler-Baddeley https://orcid.org/0000-0002-8646-1144 Principal investigator

Cardiff UNiversity Brain Research Imaging Centre (CUBRIC) Maindy Road

Cardiff United Kingdom CF24 4HQ +44 29 208 70705 Metzler-BaddeleyC@cardiff.ac.uk Public Cardiff University University/education https://ror.org/03kk7td41 Non-commercial Health and Care Research Wales http://dx.doi.org/10.13039/100012068 37448835 true fMRI investigation of the neural mechanisms of Emotional Cognitive Bias Modification as an adjunct therapy to SSRIs in depression. MILESTONE RCT Recent studies indicate that pharmacotherapy for depression is ineffective in one-third to a half of patients. Furthermore, mounting evidence suggests that antidepressant drugs (e.g., selective serotonin reuptake inhibitors, SSRIs) work best in combination with psychological therapies. There is little work, however, to determine what the minimum effective psychological intervention may be in addition to drug treatment, and a similar lack of studies examining mechanisms of action of such adjunct therapies. Processing of emotional information is critical to social functioning but is disrupted in many psychiatric disorders, including Major Depressive Disorder (MDD). We aim to investigate whether a novel Emotional Cognitive Bias Modification (CBM) psychological therapy that improves the way we see emotion in others could improve antidepressant drug efficacy. Specifically, we will deliver online CBM therapy to patients taking antidepressants, with a new episode of depression. We investigate whether this leads to changes in brain activity, assessed in an MRI scanner, that have been associated with improvements in mood in earlier work. Therapeutically, this combination of CBM and antidepressants has the potential to improve patient outcomes, and this study aims to investigate the mechanisms that may underlie this possibility. Background and study aims Depression affects people in different ways and can cause a wide variety of symptoms. They range from lasting feelings of unhappiness and hopelessness, to losing interest in the things you used to enjoy and feeling very tearful. Many people with depression also have symptoms of anxiety. There can be physical symptoms too, such as feeling constantly tired, sleeping badly, having no appetite or sex drive, and various aches and pains. Recent studies indicate that drug therapy for depression is ineffective in one-third to half of patients. Furthermore, mounting evidence suggests that antidepressant drugs (e.g., selective serotonin reuptake inhibitors, SSRIs) work best in combination with psychological therapies. There is little work, however, to determine what the minimum effective psychological intervention may be in addition to drug treatment, and a similar lack of studies examining mechanisms of action of such adjunct therapies. Processing of emotional information is critical to social functioning but is disrupted in many psychiatric disorders, including Major Depressive Disorder (MDD). We aim to investigate whether a novel Emotional Cognitive Bias Modification (CBM) psychological therapy that improves the way we see emotion in others could improve antidepressant drug efficacy. Who can participate? Persons aged 18 - 55 years who have a new or first episode of depression (defined as not prescribed an antidepressant in the previous 6 months) and have recently started taking an SSRI and able to have a type of brain scan (fMRI scan). What does the study involve? A brief (10-15 min) telephone call with a researcher to check if the study might be suitable for the participant. We would then invite the participant to an appointment (approx. 60 mins) with a researcher to discuss the study, go through a consent form, and ask the participant to complete some questionnaires. The researcher will look at the answers and tell the participant whether the participant meets the study criteria. Eligible participants will be randomly allocated to receive one of two study therapies: One group will be given a CBM (Cognitive bias modification) therapy that aims to change the way the participant interpret emotional expressions, and the other group will receive a modified version of the CBM therapy that does not aim to change your perception of expressions. We will ask participants to complete 5 online CBM therapy sessions and then have a type of brain scan (an fMRI scan) at CUBRIC (Cardiff University Brain Research Imaging Centre). Participants will be asked to complete tasks in the scanner, which will measure if there have been any meaningful changes in brain responses that we know are linked to depression Participants will be then asked to complete an online assessment 6 weeks later. At the end of the study, participants will be informed which group they were in. What are the possible benefits and risks of participating? There are several benefits to taking part. We do not know whether, and how, this kind of therapy can lead to changes in the way the brain processes information. This research will lead to a better understanding of the biological basis of depression and could help in the development of new treatments for depression in the future. Taking part in research can be interesting and rewarding, however, it is important to know that the brain scan does not form part of any medical screening, diagnosis or treatment, and so it will not benefit participants directly. Where is the study run from? Bristol Medical School (UK) When is the study starting and how long is it expected to run for? January 2020 to July 2024 Who is funding the study? Medical Research Council (UK) Who is the main contact? Professor Ian Penton-Voak I.S.Penton-Voak@bristol.ac.uk Brain activation in the amygdala in response to happy faces in comparison to rest in the amygdala, assessed by fMRI at 2 week follow-up 1. Happy versus sad comparisons in the amygdala, happy versus sad and happy versus rest in the medial and dorsolateral prefrontal cortex and occipital cortex, assessed by fMRI at 2 week follow-up 2. Mood assessments, both functional (e.g. quality of life assessments) and depressive and anxious symptoms assessed by questionnaires at 2 and 6 week follow-ups: 2.1. Revised Clinical Interview Schedule (CIS-R) - a detailed psychiatric instrument that will give an ICD10 diagnosis 2.2. Patient Health Questionnaire (PHQ-9) - a brief measure of depressive symptoms 2.3. General Anxiety Disorder questionnaire (GAD-7) - a brief measure of anxiety 2.4. Quality of Life Enjoyment and Satisfaction Questionnaire (QLES) - a brief measure of life enjoyment and satisfaction. 2.5. Snaith-Hamilton Pleasure Scale (SHAPS) - a measure of anhedonia Old ethics approval format Approved 25/11/2020, Bloomsbury Research Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8196; Bloomsbury.rec@hra.nhs.uk), ref: 20/LO/1118 10.1186/ISRCTN37448835 282861 CPMS: 47029 282861 47029 Interventional randomized controlled trial Interventional Randomised controlled trial Treatment 2024-07-31T00:00:00.000Z United Kingdom England Wales University of Bristol

School of Experimental Psychology 12a Priory Rd

Bristol England BS8 1TU Patient Current inclusion criteria as of 01/12/2022: 1. Aged 18 - 55 years 2. Have a new or first episode of depression (defined as not prescribed an antidepressant in the previous 6 months) 3. Prescribed a course of SSRI medication 4. Score >10 on the PHQ-9 assessment _____ Previous inclusion criteria: 1. Aged 18 - 55 years 2. Have a new or first episode of depression (defined as not prescribed an antidepressant in the previous 6 months) 3. Prescribed a course of sertraline medication 4. Score >10 on the PHQ-9 assessment Adult 18 Years 55 Years All 84 84 Current exclusion criteria as of 01/12/2022: 1. Prescribed an antidepressant in the previous 6 months 2. Had a course of high intensity psychological treatment in the last 6 months 3. Alcohol or substance dependency 4. Bipolar disorder, Schizophrenia/Psychosis 5. Dementia 6. Currently under psychiatric care (including those referred but not yet seen) for depression 7. Unable to access online CBM sessions (PC, laptop, phone) 8. Cannot complete questionnaires unaided or would require an interpreter 9. Are taking part in another trial involving a psychological/drug intervention 10. Have a contra indication for fMRI scanning/imaging: 10.1 Significant hearing impairment (aids cannot be worn in the scanner) 10.2 Significant visual impairment that is not corrected by glasses/contact lenses eg, double vision or loss of vision in one eye, severe cataracts 10.3 Metal objects in or around the body which cannot be removed (braces, pacemaker, metal fragments, hearing devices, accidents involving metal fragments) 10.4 History of established central nervous system disease or injury (eg, cerebro-vascular disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury) 10.5 Epilepsy, type 1 diabetes or thermoregulatory problems, including Raynaud's disease 10.6 Location sensitive tattoos to the head, neck, or genital area; (patients exceeding; tattoos covering >5% of the body; longest dimension>20cm; or multiple tattoos <20cm apart will be discussed with the radiographer). 10.7 Body Mass Index >35 kg/m² 10.8 Too physically unwell to tolerate a 30-minute fMRI scan, including musculo-skeletal disorders which make lying supine and still difficult 10.9 Claustrophobia 10.10 Pregnant or trying-to-become pregnant 10.11 We will ask participants not to take recreational drugs for 72 hours prior to each test session and not to drink alcohol for 24 hours prior to each test session _____ Previous exclusion criteria: 1. Prescribed an antidepressant in the previous 6 months 2. Had a course of high intensity psychological treatment in the last 6 months 3. Alcohol or substance dependency 4. Bipolar disorder, Schizophrenia/Psychosis 5. Dementia 6. Currently under psychiatric care (including those referred but not yet seen) for depression 7. Unable to access online CBM sessions (PC, laptop, phone) 8. Cannot complete questionnaires unaided or would require an interpreter 9. Are taking part in another trial involving a psychological/drug intervention 10. Have a contra indication for fMRI scanning/imaging: 10.1 Significant hearing impairment (aids cannot be worn in the scanner) 10.2 Significant visual impairment that is not corrected by glasses/contact lenses eg, double vision or loss of vision in one eye, severe cataracts 10.3 Metal objects in or around the body which cannot be removed (braces, pacemaker, metal fragments, hearing devices, accidents involving metal fragments) 10.4 History of established central nervous system disease or injury (eg, cerebro-vascular disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury) 10.5 Epilepsy, diabetes or thermoregulatory problems, including Raynaud's disease 10.6 Extensive or location-sensitive tattoos, defined as covering >5% of the body; longest dimension> 20cm; multiple tattoos <20cm apart; tattoos to the head, neck or genital area 10.7 Body Mass Index >35 kg/m² 10.8 Too physically unwell to tolerate a 30-minute fMRI scan, including musculo-skeletal disorders which make lying supine and still difficult 10.9 Claustrophobia 10.10 Pregnant or trying-to-become pregnant 10.11 We will ask participants not to take recreational drugs for 72 hours prior to each test session and not to drink alcohol for 24 hours prior to each test session 2021-09-15T00:00:00.000Z 2024-02-28T00:00:00.000Z Depression Mental and Behavioural Disorders Affective disorders This is a two parallel group randomised controlled trial (RCT) with allocation at the level of the individual. Participants will be randomised to treatment with SSRIs plus Emotional Cognitive Bias Modification (CBM) or SSRI plus Sham Cognitive Bias Modification. The research team aim to recruit 84 patients. Patients will be identified via local GP practices using record searches and direct referrals during face-to-face in person consultations, or telephone or videocall consultations. Those who are interested will be asked to complete a brief (approximately 10-15 minutes) telephone screening questionnaire to establish whether they would be eligible for a baseline interview (approximately 60 minutes). Suitable patients would be invited to attend a baseline appointment, arranged by the researcher. This appointment will take place face-to-face in person at the patient’s home, GP surgery, University of Bristol premises, or another mutually convenient location, where it is safe to do so and will take approximately 60 minutes. Alternatively, the appointment will take place remotely, with the patient completing online questionnaires on their own smartphone, tablet or computer, and the researcher providing support via telephone or videocall. Following informed consent, the assessment will include the completion of questionnaires to establish eligibility. Patients who meet with the researcher face-to-face in person will complete paper questionnaires. For those baseline appointments that are held remotely will complete questionnaire online using on ‘Jisc Online surveys' – an online survey tool designed for academic research (https://www.onlinesurveys.ac.uk). The data is secure and strict information security standards are followed and the data is processed in compliance with GDPR. Eligible patients will be randomised into the study and will receive either an active CBM therapy that aims to change the way the participants interpret emotional expressions, or a Sham CBM therapy, this is a modified version of the CBM therapy that does not aim to change the participants perception of expressions. Both groups will complete 4 online therapy sessions (approximately 8-12 minutes each) in the first week. This will be followed by 1 follow up appointment involving the final therapy session then participants will be offered an fMRI scan (approx 2 hours). Participants will visit Cardiff University Brain Research Imaging Centre (CUBRIC) for an fMRI scan. CUBRIC is part of Cardiff University's Science and Innovation Campus and based in Cardiff, Wales. Travel will be arranged by the research team for participants. The study will comply with the current local COVID-19 policy. Upon arriving at CUBRIC participants will be briefed about the scan and given an opportunity to ask questions. They will also perform an additional MRI safety check. This will confirm that nothing regarding the patient's medical history has changed since screening and they are still eligible for the scan. They will also need to be wearing MRI-compatible clothes. Participants will practice all 3 tasks before undergoing an MRI scan. The scan will take approx 50 minutes in total and will involve the following procedures. Resting state fMRI scan of the brain (to establish baseline functional connectivity) (5 min), face processing task (15 mins), probabilistic reversal learning task (20 mins), a full anatomical MRI scan (7 min), then n-back working memory task (5 mins). The face processing task will involve participants being presented with blocks of faces – either happy, sad or fearful faces. Participants respond by identifying the gender of the face by using the MRI-compatible button box. This will enable us to identify the neural correlates of viewing happy, sad or fearful faces. The probabilistic task will involve participants trying to determine which of two stimuli leads to reward (points gain) or loss (points deduction). This will enable us to identify the neural correlates of responding to positive and negative feedback. Finally in the n-back working memory task participants will be presented with a series of letters at the center of the screen. Participants have to respond according to whether the currently presented letter on the screen matches or doesn’t match the letter that was presented n-items. Here, there will be two blocks: 1-back and 3-back. Finally, 6 weeks later an online follow up questionnaire will be conducted (approx 15-20 minutes). Participants who are unable to complete online will be contacted and asked to complete the questionnaires by telephone or by videocall. Participants involvement then will be complete. Mixed The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. All data will be backed up immediately after generation onto the University of Bristol Research Data Storage Facility (RDSF). The RDSF provides secure, long-term storage for research data. This provides nightly backup of all data, with further resilience provided by three geographically distinct storage locations. A tape library is used for backup purposes and also for long-term, offline data storage. Only authorised users can access data stored within the RDSF. The RDSF is managed by Bristol's Advanced Computing Research Centre (ACRC) which has a dedicated steering group and a rigorous data storage policy (https://www.acrc.bris.ac.uk/acrc/RDSF_policy.pdf). The RDSF upholds and reinforces Bristol's wider Information Security Policy (http://www.bris.ac.uk/medialibrary/sites/infosec/documents/isp-01.pdf). Data will be stored in the RDSF for at least 20 years. Data on data.bris will also be stored for a minimum of 20 years. Personal data (e.g., mood questionnaire responses, MRI scans, behavioural data collected online) will be collected during this study. Participant level data on the RDSF will be based on unique numbers assigned to each participant. These numbers will be used to link data collected online to other data sources. No sensitive or identifiable information will be kept on the RDSF. Linkage between identifying information and data (fMRI, questionnaire, online collected) will instead be stored on the secure University of Bristol. Participant consent forms will include reference to the fact that participants can withdraw their data up to ten months post study completion (in order to allow time to amalgamate data before the data is made available online) and will include details regarding the long-term plans of how the data will be stored and shared. Participant contact details and a link to participant data will therefore be kept for ten months post study completion. This metadata will be stored separately, on the secure University of Bristol Experimental Psychology server, which is encrypted, and password protected. Importantly these data will be stored on a separate server to the participant data stored on the RDSF. After one year, these electronic files containing contact details will be destroyed and all data deposited on data.bris under a level of restriction that is considered appropriate, and will be anonymised. Stored in non-publicly available repository 2026 Preprint results in https://doi.org/10.64898/2026.01.27.26344720 (added 15/07/2026) Results

Added from spreadsheet

374e75a5-958a-47e5-8bc2-79a36b2fd303 4ddbff8a-4e32-4900-adc5-d79d8eea404a db1e855c-746a-4dc1-bf60-0da3caf39d3e Yes Statistical Analysis Plan ISRCTN37448835_SAP_V1.2.pdf 9f78ca27-368b-475d-a152-fc642b42e404 true application/pdf 503960 cdda5c61055c61e09ca90cb309c38332 Protocol file ISRCTN37448835_PROTOCOL_V2.0_10Nov23.pdf dc1d6011-e0da-4132-a0d7-1c8429e0fc8c true application/pdf 1171659 2e723ae9a1d85fe23f5dc42d50942a7b Ian Penton-Voak https://orcid.org/0000-0003-4232-0953 Public Scientific Principal investigator

School of Psychological Science University of Bristol 12a Priory Road

Bristol United Kingdom BS8 1TU +44 (0)117 928 8667 i.s.penton-voak@bristol.ac.uk Public University of Bristol University/education https://ror.org/0524sp257 Non-commercial Medical Research Council; Grant Codes: MR/S035648/1 http://dx.doi.org/10.13039/501100000265 44411633 true A randomised, placebo-controlled, double-blind trial of the antidepressant efficacy of a novel CNS-penetrant P2X7 receptor antagonist, JNJ-54175446, in people with major depressive disorder, an incomplete response to monoaminergic antidepressant drugs, and a biomarker profile predictive of active P2X7 signalling ATP The primary hypothesis of this study is that adjunctive treatment with JNJ-54175446 50mg qd, compared to placebo, will cause a significant reduction in depressive symptom severity measured (MADRS total score) after 8 weeks of treatment. The secondary hypotheses are: 1. Adjunctive antidepressant treatment response to JNJ-54175446, ie. Improved symptoms, fatigue and cognitive scores, will be greatest in MDD patients with peripheral biomarker evidence for P2X7-mediated inflammation. 2. Adjunctive antidepressant treatment response to JNJ-54175446 will be associated with changes in structure and function of brain reward circuit components, e.g., ventral striatum and medial prefrontal cortex, which have previously been implicated in mood disorders and the brain’s response to peripheral inflammation. 3. Anti-inflammatory effects on depressive symptom scores could be measurable within 2 weeks after start of treatment, based on clinical data suggestive of a rapid mood-lifting effect of anti-TNF antibodies in the treatment of patients with rheumatoid arthritis and “comorbid” depressive symptoms. 4. That JNJ-54175446 50mg qd will be safe and well-tolerated based on the following considerations: (i) the prior clinical safety database on JNJ-54175446, has demonstrated good safety and tolerability for similar dosing regimens in healthy volunteers and MDD patients; and (ii) the low affinity of the P2X7 receptor for ATP means that it is only activated by abnormally high levels of ATP, under stress conditions, and has no known functional role at lower, more physiological, levels of ATP. Background and study aims Depression affects over 300 million people globally and is one of the main causes of severe disability. Symptoms of depression often persist despite adequate antidepressant drug therapy, possibly because currently available antidepressant drugs have a similar mechanism of action. It is therefore important to identify new treatments that work in a different way. There is evidence to suggest that some patients with depression have increased levels of inflammation in the body. Animal studies support the link between increased inflammation and the development of a range of depressive symptoms. Hence, it is suggested that anti-inflammatory mechanisms may offer a new approach to treating depression. The aim of this study is to test whether a new anti-inflammatory drug has the potential to treat patients suffering from depression who have not responded to their current medications. This will be carried out using a series of questionnaires and clinical assessments. The researchers also wish to find out how the drug affects the body by measuring the levels of biomarkers in the blood and saliva. A biomarker is a biological molecule in the body tissues, blood or other bodily fluids that can be measured and can be used to indicate whether a process is as expected or not. The researchers will also take images of the brain to assess the effects of the drug on the brain structure and function. Who can participate? Patients aged between 18 and 60 who are currently experiencing symptoms of depression and are being treated with an antidepressant medication What does the study involve? Participants are randomly allocated to take either the new drug or a placebo (dummy) drug (one capsule a day) for about 8 weeks alongside their current antidepressant medication. Participants make 6 clinic visits to the research centre over about 14 weeks, and are also contacted by phone four times including a pre-screening phone call. Participants have to fast overnight before two of the visits. Over the duration of the trial, participants provide blood and urine samples for various tests, and undergo ECG and MRI scans (2 MRI scans). Participants also have to complete some activities at home including continuous wear of an wrist activity monitor, complete a daily sleep diary and provide saliva samples. What are the possible benefits and risks of participating? Participants may experience some improvements in their symptoms of depression. They will be compensated for reasonable travel expenses. They will receive up to £500 for their time and effort in the trial. The exact amount will depend on the number of visits completed. The drug has been tested on more than 300 people already and has been shown to be very safe. Mild side-effects that were seen include headache, fatigue and nausea. Participants will not receive any more trial drug after the trial, even if their symptoms improved during the trial. Where is the study run from? Cambridge Clinical Trials Unit (UK) When is the study starting and how long is it expected to run for? June 2018 to June 2022 Who is funding the study? Janssen Pharmaceuticals and the Wellcome Trust (UK) Who is the main contact? Elizabeth Chong Elizabeth.chong@addenbrookes.nhs.uk Depression symptoms measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and week 8 (Visit 4) 1. Depressive symptom severity measured using: 1.1. Clinician-reported scales MINI and HDRS17 at screening and baseline and MADRS at weeks 2 and 5 1.2. Participant-reported questionnaires SHAPS, QIDS-SR16, GAD-7, Chalder Fatigue Questionnaire, Perceived Stress Scale, Beck’s Depression Inventory and Childhood Trauma Questionnaire at baseline and over time at every visit until week 8 2. Suicidality assessed using the Columbia Suicidal Severity Rating Scale assessed at every clinic visit (screening, baseline visit 1, visit 2, visit 3, visit 4 and follow up visit 5) 3. Cognitive function assessed using computerised cognitive tasks designed to test for emotion-independent functions, emotion-dependent functions and sustained attention at baseline and over time at every visit until week 8 4. Stress assessed by cortisol levels in the saliva before baseline and before the last dose 5. Fatigue and activity measured using an activity monitor at baseline and over time until week 8 6. Functions of the autonomic nervous system measured by variability in heart rate at baseline and week 8 7. Brain structure and function assessed by functional MRI scan at baseline and week 8 8. Peripheral immunophenotypes measured by various biomarker assays looking at proportions of immune cells, level of cytokine release, CRP protein (marker of inflammation) levels, and gene expression at baseline and week 8 Old ethics approval format Approved 04/06/2019, East of England – Cambridge Central REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; +44 (0)207 104 8108; nrescommittee.eastofengland-cambridgecentral@nhs.net), ref: 19/EE/0035 10.1186/ISRCTN44411633 2018-001884-21 39882 2018-001884-21 39882 Randomised; Interventional; Design type: Treatment, Drug Interventional Randomised controlled trial Treatment Stopped IMP supplier withdrew support 2022-06-01T00:00:00.000Z United Kingdom England Scotland Wales Fulbourn Hospital

Elizabeth House Cambridge Road Fulbourn

Cambridge United Kingdom CB21 5EF Addenbrooke’s Hospital

Hills Road

Cambridge United Kingdom CB2 0QQ Warneford Hospital

Roosevelt Drive Headington

Oxford United Kingdom OX3 7JX Queen Elizabeth University Hospital

5th Floor Institute of Neurological Sciences 1345 Govan Road

Glasgow United Kingdom G51 4TF King’s College London

The Maurice Wohl Clinical Neuroscience Institute Cutcombe Road

London United Kingdom SE5 9RT Cardiff University Brain Research Imaging Centre (CUBRIC)

Maindy Road

Cardiff United Kingdom CF24 4HQ University Hospital Wales

Heath Park

Cardiff United Kingdom CF14 4XW Patient For a detailed description of inclusion criteria please refer to protocol section 10.1 1. Provided written informed consent 2. Between the age of 18 to 60 years inclusive 3. Meets the DSM-5 diagnostic criteria for MDD (International Classification of Diseases (ICD)-code F32.x and F33.x), without psychotic features, as confirmed by the M.I.N.I 7.0 (Mini International Neuropsychiatric Interview 7.0) 4. Has Hamilton Depression Rating Scale (HDRS) score of > = 17 5. BMI between 18 and 36 kg/m2 inclusive 6. Currently being treated with one antidepressant monoaminergic drug (e.g. SSRI, SNRI, TCA) at an adequate dose, and for at least 6 weeks and for a maximum of 24 months 7. Must be medically stable based on clinical laboratory tests, medical history, vital signs, and 12-lead ECG performed 8. Agree to practice highly effective method of birth control as stated in the protocol 9. A woman of childbearing potential must have a negative serum pregnancy test at screening 10. Agree not to donate eggs or sperm from start of dosing and for at least 3 months after receiving the last dose of study drug Adult 18 Years All 142 15 For a detailed description of exclusion criteria please refer to protocol section 10.2 1. Has a primary DSM-5 diagnosis of posttraumatic stress disorder 2. Has failed more than 3 treatments despite an adequate dose and duration, in the last 24 months 3. Loss of function allele at one or both of two SNPs on the P2RX7 gene: rs3751143 (1487 A> C) and rs1653624 (1703 T> A) 4. Has a current or recent history of clinically significant suicidality 5. Has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 12 months before screening 6. Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, cannabinoids, amphetamine/methamphetamine and ecstasy) 7. Has a current diagnosis of a psychotic disorder (e.g. schizophrenia, bipolar disorder), an eating disorder (e.g. anorexia, bulimia), or learning disability or a personality disorder that is considered by the investigator to interfere with the ability of the subject to adhere to the protocol (e.g. narcissistic personality, borderline personality disorder) 8. Has used: 8.1. Monoamine oxidase inhibitors (MAOIs) within 12 weeks before screening 8.2. Within 6 weeks prior to enrolment use of other antidepressant drugs not belonging to the allowed classes of SSRI, SNRI, or TCA. 9. Is currently treated with antipsychotic drugs (D2-antagonists; except for low-dose quetiapine), lithium, other mood stabilizers or opiates 10. Unable to complete MRI scans 11. Has current signs/symptoms of liver or renal insufficiency, diabetes mellitus (type I and II), hypothyroidism or hyperthyroidism without stable treatment, or other significant and uncontrolled medical conditions 12. Is a woman who is pregnant or breastfeeding 13. Is a man who plans to conceive a child while enrolled in this study or within 3 months after the last dose of IMP 14. Has a history of malignancy within 5 years before screening 15. Has received an investigational drug/vaccines, used an invasive investigational medical device within 60 days before the planned first dose of IMP, or has participated in 2 or more interventional clinical studies in the previous 1 year, or is currently enrolled in any drug or non-drug interventional study 16. Venous blood concentration of C-reactive protein, measured by high sensitivity assay (hs-CRP) less than 1 mg/L 2019-09-09T00:00:00.000Z 2022-06-10T00:00:00.000Z Major depressive disorder Mental and Behavioural Disorders Depressive episode, Recurrent depressive disorder Participants will be randomised 1:1 to either active drug or placebo. This will be carried out using a web-based randomisation system. Eligible participants will be randomly allocated to receive either 50 mg/day JNJ-54175446 or placebo for 8 weeks. Participants will be assessed at weeks 2, 5 and 8 using a standard clinical depression scale and the scores compared between those treated with placebo and those treated with JNJ-54175446. To understand more about the effects of JNJ-54175446 on the immune system and the brain, patients will also complete additional blood tests, questionnaires and MRI brain scans at different visits throughout the trial. Drug Phase II JNJ-54175446 The datasets generated during and/or analysed during the current study will be stored in a publically available repository. Name of repository: APOLLO (https://www.repository.cam.ac.uk/) Type of data shared: All of the individual participant data collected during the trial, after deidentification. Data will become available indefinitely after the final trial report has been submitted and following key publications. Data will be available to anyone who wishes to access the data for any purpose. Participants will be informed that de-identified trial data will become open data after the trial, and will be asked to provide their written consent. Data will be available via the Apollo website, the specific weblink is not yet known. Stored in repository

Added from spreadsheet

3ac93526-3a0e-4c03-a973-a6b39a9c6624 a905cb2f-906f-4c1c-bc50-d4fa5165a7e5 17b78f67-3eae-48d2-82bb-ba72c5ef7b42 94782eba-9461-468a-9c4f-613604d1b4b3 9e0ce9fd-5ad0-4c12-b812-ec04ea3a52ee 4f2f6290-d2ed-48a2-a97c-69a4e43060c6 bd34db13-2ec9-494b-a5cf-c19e82badc9f Yes Elizabeth Chong Public

Cambridge Clinical Trials Unit Coton House Level 6, Box 401 Addenbrooke’s Hospital Hills Road

Cambridge United Kingdom CB2 0QQ +44 (0)1223 254919 Elizabeth.chong@nhs.net Public Edward Bullmore https://orcid.org/0000-0002-8955-8283 Scientific

University of Cambridge Department of Psychiatry Herchel Smith Building for Brain & Mind Sciences Cambridge Biomedical Campus

Cambridge United Kingdom CB2 0SZ +44 (0)1223 336583 etb23@cam.ac.uk Public Rachel Lee Public

Cambridge Clinical Trials Unit Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital Coton House Level 6, Flat 61 Hills Road

Cambridge United Kingdom CB2 0QQ +44 (0)1223 254919 rachel.lee@addenbrookes.nhs.uk Public Cambridgeshire and Peterborough NHS Foundation Trust Hospital/treatment centre https://ror.org/040ch0e11 Non-commercial University of Cambridge University/education Non-commercial Janssen-Cilag Ltd; Grant Codes: RNAG/374 Wellcome Trust; Grant Codes: RNAG/375 http://dx.doi.org/10.13039/100004440