Serris, France

ARISTOCRAT: Blinded Trial of Temozolomide +/- Cannabinoids

This is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to compare the cannabinoid Nabiximols (Sativex®) with placebo in patients with recurrent MGMT methylated glioblastoma treated with temozolomide (TMZ). The trial will randomise a target number of 234 patients on a 2:1 basis to receive either Nabiximols or Nabiximols-matched placebo, in combination with standard TMZ. Patients will be followed up at 4-weekly assessments for a minimum of 52 weeks from the start of trial treatment or until death, whichever is sooner. MRI scanning will be performed at screening, week 10, week 22, week 30, then 3-monthly after commencing trial treatment as per standard practice. The trial includes an initial feasibility study of 40 patients to confirm safety, compliance and achievability of planned target recruitment. There are no formal criteria for evaluation of feasibility but once 40 patients have been recruited, the independent Data Monitoring Committee will review the adverse event data, details on protocol treatment received, monthly recruitment rates and projected recruitment in order to make recommendations on trial continuation. The current phase II trial design will enable potential expansion of recruitment into a phase III trial, should the emerging phase II results warrant this development. The trial will be linked to the Tessa Jowell BRAIN MATRIX (TJBM) programme; utilising TJBM infrastructure, opening the same participating sites, and aligning the data collection and Quality of Life assessments already embedded in TJBM. This collaboration will allow data sharing within the platform thereby streamlining patient entry and provide additional oversight through TJBM. Patients recruited to TJBM who are potentially eligible for ARISTOCRAT may be identified and suggested to sites for consideration to the trial.

Exactech Shoulder Post Market Clinical Follow-up Study

Hemithyroidectomy or Total-Thyroidectomy in 'low-risk' Thyroid Cancers

GEKO Venous Thromboembolism Prevention Study

Venous thromboembolism (VTE) is a disabling and potentially fatal outcome that may be acquired after having a stroke. The standard treatment to prevent the development of VTE is to give anticoagulation medication. However, this is not recommended in the UK after stroke. Instead the recommended treatment is Intermittent Pneumatic Compression (IPC), where cuffs placed around the lower legs are filled with air to help squeeze the legs and induce blood flow. However, not all patients are able to receive or tolerate IPC treatment. Another treatment which has shown promising results to prevent VTE in immobile patients after stroke, is with a medical device called the geko™ device. The geko™ device is a CE marked medical device which means the manufacturer has checked that the device complies with the essential safety and performance requirements for its' intended use which is to increase blood circulation to help prevent VTE. The aim of this study is to determine if the geko™ device is more effective at preventing VTE in immobile acute stroke patients, than the current IPC standard of care treatment. Following the consent process, stroke patients will be randomised to receive either IPC or geko device. Both devices will be applied until the patient can walk again without help, or for a maximum of 30 days. A compression Doppler exam of the legs will be conducted after 7 days or at discharge if the patient recovers earlier (optional) and after 14 days (mandatory). At 14 days post-randomisation, a patient questionnaire about the comfort of the device, as well as additional health information will be collected. At 30 days after randomisation, additional information about symptomatic DVTs or PEs etc., will be collected from the participant's medical notes. A final follow-up will then be conducted over the phone after 90 days to find out about the patient's recovery, health, mobility and quality of life.

Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study)

Part A will assess the efficacy, safety, and tolerability of the combination of B mg zibotentan and 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with features of portal hypertension and with no history of decompensation events. If the safety profile is determined to be acceptable at the conclusion of Part A, Part B will investigate efficacy, safety, and tolerability of A mg, B mg, or C mg zibotentan combined with 10 mg dapagliflozin and of 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Part B will include a broader range of Child- Pugh A and Child-Pugh B cirrhosis participants, including those with more severe disease, a history of decompensation events, or current ascites. The study will be conducted in approximately 30 to 45 study centres in North America, Asia, and Europe.

Who Benefits Most From Cognitive Rehabilitation for Multiple Sclerosis?

Preliminary Randomised Evaluation of Singing in Dementia

PURPOSE The purpose of PRESIDE is to test the feasibility of conducting a randomised trial of community singing in dementia that investigates the effects of singing on quality of life and explores the impact singing groups have on the relationship between the person with dementia (PwD) and carer. PRIMARY OBJECTIVE The primary objective of the PRESIDE study is to test the protocol for a two-arm, parallel group superiority randomised trial of community singing in dementia with a waiting-list control design. The relevant indicators are recruitment, retention, and the acceptability of the trial design. SECONDARY OBJECTIVES The secondary objective of the study is to explore the impact of group singing on PwD and their carers. This would improve understanding of the mechanisms of action in group singing for PwD and potentially indicate suitable outcome measures for full-scale trial. DATA COLLECTION A mixed-method design will be applied to collect data using questionnaires, semi-structured interviews and observations. PRIMARY END POINT The attainment of the feasibility criteria at 6 months is the primary end point for PRESIDE. Proposed criteria for proceeding to a full trial: 70% recruitment; 70% retention of participants over 3 months; and acceptability of waiting-list controls shown by 70% singing group take-up post waiting-list period. SECONDARY ENDPOINT The secondary endpoint is the measurement of social independence, loneliness, quality of life, activities of daily living, mood, musical engagement and cognition of PwD; the measurement of quality of life, loneliness, mood, caring relationship and experience of carers. Each dyad's use of health social care services and resources will also be documented. Follow-up data will be collected at 3 months after baseline to compare the difference between the intervention and control groups, and 6 months to investigate the sustainability of any treatment effect. Further, to better understand the experiences of dyads who attend the singing group, qualitative data will be collected using interviews and participant observation. STOPPING RULES AND DISCONTINUATION The intervention will be stopped if a Serious Adverse Event (SAE) occurs which is judged to be directly related to the trial and likely to affect other participants. This decision will be taken by the DMEC. Individual participants may withdraw from the trial at any time and their reasons for withdrawal will be recorded if they are willing to give them. The Trial Steering Committee would decide whether to continue if recruitment figures were poor. RANDOMIZATION AND BLINDING Participants will consist of a PwD and their carer, with stratification on MMSE score and minimisation on age, sex and MusEQ score. Baseline data will be collected by members of the Clinical Research Network (CRN) for all recruited pairs prior to randomisation. Randomised pairs will be assigned to either the intervention group or the waiting-list control group. Follow-up data collection at 3 and 6 months will be undertaken by members of the CRN, who will be blind to group allocation. However, there is the possibility that since the study participants will know their own allocation, they may reveal this during the follow-up data collection. Any unblinding of outcome assessors which occurs in this way will be recorded, as it has implications for the feasibility of the study design. Randomisation will be performed by a web application created by the trial programmer at the University of Nottingham Stroke Trials Unit, using web and database servers provided by University of Nottingham Information Services (IS). The research team will be divided in the data management group, who will not be blinded to group allocation (intervention or waiting list control) for logistical reasons (data collection, anonymising data and running of the study), and the analysis group, who will be blinded throughout the study and have no contact with study participants. Allocation will only be revealed to blinded members of the research team in the case of emergencies (i.e. SAEs). In this case the Chief Investigators and Data Monitoring and Ethics Committee will be informed. PARTICIPANT AND STUDY DURATION The study will last two years. Participant involved is anticipated to be between 9 and 12 months. The end of the trial will be the final assessment of the last participant with dementia and their carer. After recruitment and baseline data collection, participants will either attend a singing group for ten weeks or wait for 12-13 weeks before attending a singing group for ten weeks. They will receive follow up at 3 months and 6 months after baseline. RECRUITMENT Recruitment will be multi-channelled: PRESIDE posters and a cover letter will be sent for distribution to people who have recently been diagnosed with dementia via NHS Memory Assessment Services and PwD who are currently on the waiting list for Singing for the Brain sessions via the Alzheimer's Society. Local community organisations, charities and local press (Radio Nottingham, Nottingham Post and similar) will also be utilised, and social media advertising will be part of the recruitment campaign. Recruitment will be undertaken using the online platform "Join Dementia Research". Regional recruitment may also take place through having PICs within primary care, with the support of the NIHR CRN for GP surgeries. Eligible participants will be screened from a database by a member of the direct care team at that practice. Participants that meet the inclusion and exclusion criteria will be invited to join the study through letter invitation from their GP surgery. Participants who contact the research team post invitation, will then be provided with study specific information by the research team. Participants may contact the research team directly to express interest in taking part in the study, for example, in response to advertisement. EXPRESSION OF INTEREST AND PARTICIPANT INFORMATION Potential participants who are eligible and interested in taking part will receive a PRESIDE Participant Information Sheet (PIS). They will have the opportunity to read the information and to speak to members of the research team. If they wish to proceed with involvement in the study, they will receive a visit from a PRESIDE research member. This will take place at a convenient location, such as their home or other venue. The researcher will fully explore the implications of participation in the study and confirm their eligibility. They will be provided with a consent form which they will sign if they choose to continue with participation. Following consent, the researcher will enrol the participant dyad and complete baseline outcome measures at the same visit. The research or their nominee (such as the participant's usual care team) will inform the participant, of all aspects pertaining to participation in the study. If needed, the usual hospital interpreter and translator services will be available to assist with discussion of the trial, the PIS, and consent forms. However, consent forms and information sheets will not be available in other languages since understanding English is an inclusion-criteria for this study. It will be explained to the potential participant that entry into the trial is entirely voluntary, that their treatment and care will not be affected by their decision and that they can withdraw at any time. Participants will be made aware that should they withdraw, anonymised data already collected cannot be erased and may still be used in the final analysis. REMOVAL OF PARTICIPANTS AND PARTICIPANT WITHDRAWAL Temporary discontinuation might happen if either participant (PwD or carer) from the dyad is unavailable, indisposed or does not want to join the session on a specific day. Participants may withdraw from the study at any time, without providing any reason. Carer participant withdrawal would result in the participant with dementia being re-paired with a different person. Withdrawal from a PwD. would result in withdrawal of the dyad. However, the carer participant would still be able to attend the allocated singing sessions if they wished. Participants may also be withdrawn from the study at the discretion of the Investigator. Participants who have lost capacity to consent but have remained part of the study (see section on Informed Consent below) will be immediately and permanently withdrawn from the study if they show observable signs of dissent or discomfort or it is reported from their carer. Participants will be made aware that withdrawal will not affect their future care. Abrupt termination of the study is unlikely to affect the participant safety as the study focus on an entertainment social intervention. Failure to recruit sufficient participants could lead to termination of a specific regional group. In this instance, participants would be offered another group to join. INFORMED CONSENT The Consent Form will be signed and dated by the participant before they enter the trial. PIS and, when appropriate, a dementia friendly booklet will be provided for PwD and carers. Fully informed consent will be taken at the initial study visit by trained and experienced members (CRN or PRESIDE) that hold a valid Good Clinical Practice Certificate (NIHR). Absolute care will be taken to ensure that participants fully understand the study and their involvement. PwD who do not have capacity to provide informed consent at the start of the study will be excluded from the study. Due to the progressive nature of dementia, Dewing's 'process consent model' is applied so there is periodical assessment of capacity and consent is continuous and ongoing. If a participant with dementia loses capacity during the trial period, where appropriate, the carer participant in the dyad would be asked to act as consultee. If the carer participant is a paid carer, then this would not be appropriate and a consultee declaration from the most appropriate person for this individual would be sought. The consultee will be provided with information about their role within the parameters of the study and will be asked to make a judgement about whether they would have wanted to continue to take part in the study. If they judge that the PwD would have wanted to continue to take part, the consultee will sign a declaration form to indicate this. In the unlikely event that a PwD was judged to have regained capacity during the trial period, the research team would discuss with them to ascertain whether they wished to continue in the study. We shall treat the consent of carers equally rigorously. Should a carer lose capacity to consent during the trial period, a consultee will be sought for them. In this situation, the continuation of a dyad in the study will be at the CI's discretion. METHODS Data analysis will be conducted by a statistician using Stata 16 software. All measures will be summarised with mean (S.D.) for normally distributed variables, median (IQR) for skewed variables and frequency (%) for response of categorical variable, by intervention arm across follow-up time. ANCOVA will be performed to quantify treatment effect size and its precision by means of regression modelling with baseline measures as covariate, and to derive the change from baseline score for each arm. Due to the non-independence of patient-carer dyad measures and data being measured repeatedly, multivariate multilevel modelling will be performed to account for the association between same kind of outcome measure of patient-carer data and repeated data. Data will calculate recruitment rate, retention rate and attrition rate, exploring patterns of missing data and drop out from the waiting list control group. All results will be used to inform future definitive trial design. All data will be analysed on UoN computers and backed up to the UoN servers.

Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1)

This is a Phase 3, open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with advanced (inoperable) or metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy. Gedatolisib is an intravenously administered pan-PI3K/mTOR inhibitor. Palbociclib is a CDK4/6 inhibitor. Fulvestrant is a selective estrogen receptor degrader (SERD). Subjects will be assessed for PIK3CA status and then randomized to treatment arms according to their confirmed PIK3CA mutation status.

Neuromelanin MRI: A Progression Marker in Early PD

Parkinson's is the second most common neurodegenerative disorder with progressive, disabling motor and non- motor symptoms for which effective symptomatic, but non disease-modifying treatment is available. Neuromelanin- containing neurons in the substantia nigra undergo neurodegeneration during Parkinson's disease. There is considerable heterogeneity in the progression of cell loss and clinical symptoms with major research interest in identifying prognostic subtypes. A non-invasive biomarker that can track the loss of the neuromelanin-containing neurons would be highly desirable to (i) study subtype-specific trajectories of SN depigmentation, (ii) track disease progression in early Parkinson's to assist in stratifying groups and outcome assessment in clinical intervention trials, and (iii) enable patients and their families to better manage their condition including informed forward planning. Neuromelanin MRI (NM-MRI) is a new approach sensitive to the neuromelanin-iron complex, with proven association with the tissue changes of the number of the neuromelanin-containing neurons. Its diagnostic value was established in several studies case-control, but there is a lack of standardisation, multi-centre studies and prospective diagnostic trials. To date only a small, single arm retrospective study reported serial NM loss in Parkinson's. Building on our previous work, the proposed research entails the development of an early progression biomarker for Parkinson's disease that is pathologically relevant, non-invasive, and uses MRI which is a widely available imaging method for detection. The experimental approach combines advanced computational imaging, retrospective use and extension of existing cohorts with a new dedicated prospective serial study using NM-MRI in uncertain parkinsonism, de novo and early Parkinson and healthy controls using latest MRI technology.

A Trial of 5 Fraction Prostate SBRT Versus 5 Fraction Prostate and Pelvic Nodal SBRT

This study will look at the safety of curative radiotherapy to the prostate and lymph glands given in 5 visits, in men with high risk localised prostate cancer. The purpose of the research is to test an advanced type of external beam radiotherapy called stereotactic body radiotherapy (also known as SBRT) in 1128 participants with high risk localised prostate cancer (that is, prostate cancer that has not spread beyond the prostate gland but is at high risk of growing quickly or spreading). Importantly, this treatment delivers a potentially curative dose of radiotherapy in only 5 treatments over two weeks. Half the participants in the trial will receive radiotherapy to the prostate, the other half will have radiotherapy to the prostate as well as the surrounding lymph nodes. The investigators will follow patients in the trial for at least three and half years to see which treatment is best. The investigators will be looking at whether it is safe to give this treatment by reviewing any side-effects that occur and also assessing whether giving SBRT to the lymph nodes as well as the prostate reduces the chance of prostate cancer returning. The treatment will take place at NHS radiotherapy centres that are experienced in giving SBRT and radiotherapy to the pelvic nodes, and have been quality assured to deliver these treatments