Bracken Rd, Sandyford Industrial Estate, Ireland

3T MRI of Intramedullary Spinal Cord Tumours

Clinical Study of Antibody-Drug Conjugate MYTX-011 in Subjects With Non-Small Cell Lung Cancer

The study will be conducted in 2 parts. Part 1 will assess the safety and tolerability of MYTX-011 and identify the dose to be studied in Part 2. Part 2 will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations, populations with a current unmet medical need.

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.

IMPase in Treatment-resistant Depression

Ebselen, a potential new drug for treatment resistent depression (TRD). Clinical depression is an important public health problem, associated with an even greater burden of illness than other common diseases such as angina, arthritis, asthma, and diabetes. The burden of illness is particularly high for depressed patients in specialist psychiatric care who often fare poorly with current treatments and who typically experience substantial functional disability with a significantly increased risk of suicide. A limiting factor in improving outcome for such patients is the lack of acceptable pharmacological approaches for so-called 'TRD'. In a recent large randomised trial, even specialist mood disorder services with access to expert psychological and pharmacological treatment, struggled to improve therapeutic response rates compared to 'treatment as usual'. This indicates that improving the management of TRD requires more than improved access to specialist clinics - new, more effective and better tolerated therapies are needed. The principal aim of the current study is to examine the utility of a potential new lithium-mimetic drug, ebselen, in patients with TRD. Lithium itself is known to be efficacious in the management of TRD as an 'add-on' treatment to ineffective antidepressant medication. However, its poor tolerability and safety and the need for regular blood tests has resulted in it having a low acceptability for both patients and clinicians. Lithium has many pharmacological targets but inhibition of an enzyme called inositol monophosphatase (IMPase) is an important candidate for its therapeutic effects in mood disorders. However, this potential mechanism has not been tested previously in depressed patients. Ebselen is an organoselenium compound, developed originally as an antioxidant for use in neuroprotection, post-stroke. Although clinical trials indicated that ebselen was safe and well-tolerated, its therapeutic activity in stroke patients was limited and its commercial development was halted. Subsequent work in the University of Oxford's Department of Pharmacology found that ebselen is a bioavailable and brain penetrant inhibitor of inositol monophosphatase (IMPase) (Ki ≈ 1 μM) (8). This finding provides an opportunity to use ebselen as a means of testing the role of IMPase inhibition in the therapeutic effect of lithium in TRD. Recently, experimental medicine models developed in the University of Oxford's Department of Psychiatry have shown promise in describing early surrogate markers of patient responsiveness to antidepressants. Traditionally, the translation of novel potential antidepressant compounds from animal studies to humans has involved placebo-controlled clinical trials that are expensive and take many years. The newer, more experimental medicine studies exploiting the use of surrogate markers for depression and antidepressant drug action have the potential to transform this field and refine development decisions while minimising time and cost and burden on patients. The surrogate markers of antidepressant efficacy that the investigators have developed for this process are based on cognitive theories of depression and antidepressant action. Cognitive theories of depression outline the role of negative emotional biases in information processing in the aetiology and maintenance of the disorder. For example, compared to controls, depressed patients are more likely to perceive ambiguous facial expressions as negative and to retrieve negative self-relevant information in both explicit and indirect memory paradigms. These cognitive biases are believed to play a key role in the persistence of the depressed state because increased accessibility of negative perceptions and memories maintains and exaggerates the depressed mood leading to a self-perpetuating cycle. Importantly, cognitive biases shift early in antidepressant treatment, and positive changes in emotional processing can be demonstrated in relatively small groups of patients. Subsequent studies showed that early positive shifts in emotional processing predict eventual therapeutic outcome to antidepressant medication. The investigators have previously used these experimental medicine approaches to assess the effects of ebselen in healthy volunteers. The investigators found that, given at a dose of 600 mg, as well as 1200 mg twice daily, ebselen produced a greater recognition of some positive emotions, an effect the investigators have noted with numerous typical and atypical antidepressants and a strong predictor of clinical antidepressant activity. The investigators also utilised magnetic resonance spectroscopy (MRS), and demonstrated a reduction in brain inositol after treatment with ebselen. This provides evidence for IMPase target engagement of ebselen at the dose proposed for this study. Therefore, the investigators now have substantial data that indicates that ebselen is a valid means of testing IMPase inhibition as a potential antidepressant mechanism in a clinical population of TRD patients, using an experimental medicine approach.

vHDU Phase 5: Impact of an Ambulatory Monitoring System on Deterioration Detection and Clinical Outcomes

The primary objective of this study is to assess the impact of ambulatory monitoring systems (AMS) integration (with active clinical alerts) versus standard care in deterioration detection. Secondary objectives include other deterioration detection and clinical outcomes, trial progression outcomes, staff impact and alerting system performance, overall system reliability and patient experience. This study is a superiority feasibility randomised controlled trial with two-arm parallel groups and 1:1 allocation ratio to compare the use of an ambulatory monitoring system with standard care in hospitalised patients. This feasibility trial will be conducted not only to assess the impact of AMS on early deterioration detection and other clinical outcomes but also to explore recruitment rate, calculate required sample size, number of sites and recruitment period for a full definitive RCT. Participants will be recruited in one or more surgical wards inside Oxford University Hospitals NHS Foundation Trust (to be decided during feasibility trial, dependant on recruitment rate). Patients will be screened, recruited and participate in this study throughout their hospital stay, no follow-up visits will be required. The intervention consists in the use of AMS that also includes an alerting system. Participants will wear one pulse oximeter (WristOx2 3150 OEM BLE, shorted to "Nonin", hereafter) measuring pulse rate (PR) and oxygen saturation (SpO2), one chest patch (VitalPatch) that will continuously measure their heart rate (HR), respiratory rate (RR), temperature,; and one A&D UA-1200 BLE Blood Pressure device, intermittently measuring systolic and diastolic blood pressure, and pulse rate. Clinical staff will be able to access and interact with real-time vital signs through a dashboard style display and will be alerted via a hand-held device, and/or dashboard, according to the patient's EWS score. The control group will also be fitted with these devices. However, clinical staff will not be able to access the dashboard display or receive alerts. The trial will include a calibration period inside a surgical unit were the investigators will refine out alerting system. During this period the investigaotors will optimise our alerts through continuous analysis and feedback from the relevant clinical teams. Randomisation will still be conducted during this period. This feasibility trial will be conducted in surgical units at the John Radcliffe Hospital, Oxford University Hospitals (OUH) NHS Foundation Trust. This will: - Assess the feasibility of a definitive RCT - Support sample size calculation for full study - Assess recruitment rate and the need for inclusion of more wards inside OUH.Staff focus groups or interviews will be held to gather feedback on the system which may inform further refinements, including usability, perceived effect on workload and appropriateness of alerts. - Multi-professionals staff interviews with be held to assess staff perception of the acceptability of the system in clinical practice. Patients interviews will be held with patient who have worn the monitoring, to gain their perceptions of the system, including wearability, sense of safety and potential improvements.

Staphylococcus Aureus Network Adaptive Platform Trial

Infection of the bloodstream with the bacterium Staphylococcus aureus (Staphylococcus aureus bacteraemia, SAB) is a serious infection that results in 15-30% of affected patients dying within three months of acquiring the infection. Treatment of this infection requires patients to be hospitalised, treated with prolonged antibiotics through an intravenous line, and carefully examined for the occurrence of complications associated with this condition. At present, there are many treatment options in current use, with no clear agreement as to which of these is best. The SNAP trial aims to identify which treatment options for SAB results in the fewest patients dying within the first 90 days after an infection. In contrast to a conventional clinical trial, the SNAP trial will examine multiple different treatment options at once. Patients will be randomly assigned to different concurrent treatment options currently considered acceptable in routine medical care, but as the trial progresses, more patients will be assigned to treatments that appear to have better outcomes than those with worse outcomes. The trial will adapt to accumulating trial evidence, on a regular basis, by removing treatment options found to be inferior, incorporating new treatment options, and ensuring that all patients in the trial receive the best treatments once they have been identified. Over time, we hope to determine the best combination of treatment options for patients with SAB. The SNAP Trial infrastructure will also support a number of sub-studies. A list of all active sub-studies can be found on the SNAP website: https://www.snaptrial.com.au/substudies.

Axillary Management in Breast Cancer Patients with Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease. Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years. Methods: Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness. Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years. Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated. Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)

Mucus hypersecretion is a clinical feature of BE. This mucus-retention aids bacterial infection that can lead to pulmonary exacerbations, which further develops the "viscous cycle" of mucus-retention, infection, inflammation and tissue damage. Mucoactive drugs target this cycle by potentially increasing the ability to expectorate sputum and/or decrease mucus hypersecretion. The current guidelines indicate that mucoactives in combination with airway clearance may be considered to enhance sputum expectoration in BE, but the evidence to support their use is limited. Furthermore, evidence for the effectiveness of hypertonic saline (HTS) and carbocisteine is insufficient to recommend them within the management of BE. However, EMBARC/BRONCH-UK data show that BE centres do prescribe mucoactives. This is important because adherence to therapies in BE in general is low, decreases as the number of prescribed medications increases, and is also related to poorer patient outcomes, including the number of pulmonary exacerbations and quality of life. Therefore, it is essential that only those drugs that are effective should be prescribed for patients with BE. There are cost considerations associated with mucoactives, and there is a risk of polypharmacy side effects. Unlike BE, relatively strong evidence exists to favour the use of both HTS and carbocisteine within other respiratory conditions. Therefore, this trial will answer important clinical questions about whether similar benefits can be demonstrated in BE by using a pragmatic design to explore the specific effects of mucoactive agents, and directly support, or refute, more targeted use of these drugs. Patients will be randomised to one of four treatment groups: (i) standard care and twice daily nebulised HTS (6%), (ii) standard care and carbocisteine, (iii) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (iv) standard care alone.

MultiOrgan Multi-Parametric MRI Study