Stevenage

An open-label, controlled, multi-site, interventional, 2-arm, Phase II/III trial of BNT113 in combination with pembrolizumab vs pembrolizumab monotherapy as first line treatment in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing programmed cell death ligand-1 (PD-L1) with combined positive score (CPS) ≥1. This trial has two parts. Part A, is an initial non-randomized Safety Run-In Phase to confirm the safety and tolerability at the selected dose range level of BNT113 in combination with pembrolizumab. Part B, is a randomized part to generate pivotal efficacy and safety data of BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy in the first line setting in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing PD-L1 with CPS ≥1. Patients included in the Safety Run-In Phase of the trial (Part A) will not be randomized to Part B and will continue on-trial treatment (BNT113 plus pembrolizumab) within Part A. For Part B, an optional pre-screening phase is available for all patients where patients' tumor samples may be submitted for central HPV16 DNA and central PD-L1 expression testing prior to screening into the main trial. Patients will be treated with BNT113 in combination with pembrolizumab or with pembrolizumab monotherapy for approximately up to 24 months.

This is a Phase III, two-arm, randomized, double-blind, global, multicenter study assessing the efficacy and safety of rilvegostomig compared to pembrolizumab as a 1L treatment for patients with mNSCLC whose tumors express PD-L1.

This is a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of DMX-200 in patients with FSGS. The duration of the double-blind period per patient is estimated to be maximum of 122 weeks, a Screening and Qualification period of between 6 and 14 weeks (including a 4 week period to complete the assessments required for Screening, Titration (if required, up to 4 weeks) and, 6-weeks of Stabilization, a 104-week Treatment period, and up to a 4-week off-treatment Follow-up period. The treatment duration of the OLE period per patient is estimated to be a minimum of 104 weeks (2 years) with a 4-week off-treatment Follow-up period. The total study duration (double-blind period and OLE combined) is currently estimated to be a minimum of 230 weeks.

The main purpose of this study is to compare the disease-free survival (the length of time after randomization that a participant survives without any signs or symptoms of the cancer returning, or progressing) between Bacillus Calmette-Guérin (BCG) treated participants receiving treatment with TAR-210 versus investigator's choice of intravesical chemotherapy for treatment of high-risk non-muscle-invasive bladder cancer (HR-NMIBC).

The risk of a clot forming in a blood vessel, which can cause a heart attack or stroke, is determined partly by how "sticky" the blood is and partly by the effectiveness of the natural defences in the blood in dissolving any clots that start forming (clot lysis, or "fibrinolysis"). There are available tests that can assess how "sticky" the blood is, and we can overcome that with specific blood-thinning medications (such as anticoagulants \[such as warfarin, apixaban, rivaroxaban\] and antiplatelet agents \[such as aspirin and clopidogrel\]). However, we have not been able to assess the effectiveness of natural clot dissolving mechanisms, until recently. In the last few years, using new blood testing techniques, we and other groups, have shown that individuals who have less effective natural clot lysis, have a much higher risk of heart attack, stroke and death. Therefore, we would like to find medications that can make clot lysis more effective, in such individuals, to reduce their risk of stroke and heart attack. Unfortunately, most blood thinning tablets for long term use do not improve clot lysis. Earlier, our group has shown that the anticoagulant apixaban, mildly improved clot lysis. We would now like to assess clot lysis in patients taking apixaban and compare it to patients taking a very new type of anticoagulant called asundexian, to see if asundexian can improve clot lysis more than apixaban. The easiest way to do this, is to test additional blood samples from patients who are already taking part in a clinical trial comparing apixaban and asundexian (OCEANIC-AF). OCEANIC-AF is a phase 3, multicentre, randomised clinical trial, comparing asundexian, a new type of blood thinner (factor XI inhibitor) with a commonly used blood thinner (apixaban, a factor X inhibitor), to see if it carries a lower risk of bleeding. This is a prospective observational linked study to the main OCEANIC-AF study, to be undertaken in 2 centres in England. Patients enrolled in OCEANIC-AF at these 2 centres will have 4 additional blood samples taken, at baseline before starting the investigational drug or comparator, then at the 3, 6 and 12 month visits.

The research study is being done to see if ziltivekimab can be used to treat people who were admitted to hospital because of a heart attack. Ziltivekimab might reduce development of heart disease, thereby preventing new heart attacks or strokes. Participants will either get ziltivekimab (active medicine) or placebo (a dummy medicine which has no effect on the body). Which treatment participants get is decided by chance. The chance of getting ziltivekimab or placebo is the same. The participant will need to inject the study medicine into a flat skin surface in there stomach, thigh, or upper arm once every month. Ziltivekimab is not yet approved in any country or region in the world. It is a new medicine that doctors cannot prescribe. The study will last for about 2 years.

The risk of a clot forming in a blood vessel, which can cause a heart attack or stroke, is determined partly by how "sticky" the blood is and partly by the effectiveness of the natural defences in the blood in dissolving any clots that start forming (clot lysis, or "fibrinolysis"). In the last few years, using new blood testing techniques, we and other groups, have shown that individuals who have less effective natural clot lysis, have a much higher risk of heart attack, stroke and death, even despite current best medications. Therefore, we would like to find medications that can make clot lysis more effective, in such individuals, to reduce their risk of stroke and heart attack. Unfortunately, most blood thinning tablets for long term use do not improve clot lysis. Earlier, our group has shown that the anticoagulant apixaban, mildly improved clot lysis Elevated concentration of Lp(a) in the blood is a risk factor for the development of cardiovascular disease including coronary artery disease and narrowing of the aortic valve. Lp(a) may exert its adverse effects by impairing fibrinolysis. Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. Lp(a) has a high degree of homology to plasminogen (a pro-enzyme that is cleaved to form plasmin) and may cause thrombosis by competitively inhibiting t-PA-mediated plasminogen activation and tPA-mediated clot lysis. Furthermore, Lp(a) stimulates the activity of PAI-1, which is the major inhibitor of the fibrinolytic system. Until recently, Lp(a) has been considered a non-modifiable cardiovascular risk factor as few therapies are available to sufficiently reduce Lp(a) levels. New data, however, have shown that novel cholesterol lowering treatments, namely PCSK9 inhibitors and inclisiran (a long-acting silencing RNA) can reduce Lp(a) levels by approximately 20-25%. Given Lp(a) is a causal risk factor for cardiovascular outcomes, it is important to know if a reduction in Lp(a) can favourably modify endogenous fibrinolysis. If Lp(a) level is directly related to the effectiveness of endogenous fibrinolysis, then medications that reduce Lp(a) (currently PCSK9i and/or inclisiran, and others in development) could be used as targeted treatment for patients who despite optimal antithrombotic therapy, demonstrate impaired endogenous fibrinolysis.

People with severe kidney failure need treatment by dialysis or transplantation to stay alive. In the UK there are 25,000 people receiving treatment with haemodialysis (HD). Conventional haemodialysis works on the principle of diffusion for removal of toxins. Haemodiafiltration (HDF) is a technique of dialysis which implies the principle of convection in addition to diffusion. Large clinical trials comparing haemodiafiltration with conventional haemodialysis have reported better survival in patients having haemodiafiltration with large convection volume. The mechanism of survival benefit with high convection volume remains unclear. The investigators hypothesize that the benefit of high convection volume haemodiafiltration is due to enhanced removal of large sized toxins called 'middle molecules'. Additionally, it may also be due to better blood pressure control and less inflammation when dialysing using this technique. The literature so far has been inconsistent to confirm this. Understanding the relationship of haemodiafiltration convection volume with middle molecules removal and clinical parameters is crucial for adoption of this mode of treatment. Additionally, it can potentially transform the presently imperfect dialysis prescription based on small molecule removal to clinically relevant middle molecules removal. In this single centre cross sectional study, the investigators aim to recruit 400 adult participants who have been on haemodiafiltration for at least 3 months. Once consented, the participants will be observed in a single routine dialysis sessions (study visit) to record all the standard care clinical parameters and dialysis related information including dialysis convection volume from haemodiafiltration. Participants will also have routine blood tests at the start and end of the observed dialysis session and additional blood tests to measure the removal of middle molecules at the same time. The relationship of these observed clinical and measured toxins removal parameters with convection volume will be determined from the collected data.

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.

Haemodialysis is essential for patients with End-Stage Renal Disease (ESRD), requiring consistent vascular access through arteriovenous fistulas or grafts. This involves frequent needling, a procedure that is painful and distressing for many patients, causing significant emotional and physical demands on healthcare professionals working in the dialysis units. In the UK, about 30,000 patients receive haemodialysis, involving over 300 needling procedures annually. Healthcare professionals (Registered nurses and healthcare assistants) play a crucial role, with their expertise directly affecting patient outcomes. However, 60% of HCPs (healthcare professionals) report high job-related stress, particularly due to needling demands. Effective needling requires not only technical proficiency but also managing patient pain and anxiety. Strong staff-patient relationships, characterized by empathy and understanding, can enhance the needling experience. Challenges for dialysis unit staff includes the technical difficulty of needling and the emotional burden of patient care. Studies highlight the need for better training and support systems to help them cope with these demands. Understanding healthcare professionals' perspectives can identify areas for improvement, inform training programs, and improve experiences in dialysis units. Research by Rahmah et al. (2018) and Duncanson (2023) emphasizes the importance of HCPs skills and the psychological toll on them, suggesting further exploration of this area is needed. The primary aim of this research is to examine HCPs perspectives on the needling experience in haemodialysis, aiming to identify improvement areas and inform targeted training programs to enhance patient experiences. The study will utilize a qualitative exploratory design with semi-structured interviews to gather in-depth insights from HCPs. Data will be collected from renal dialysis units at East and North Hertfordshire NHS Trust, involving 12 to 16 registered nurses performing needling procedures. Thematic analysis will be used to analyse interview transcripts and identify key themes related to technical skills, communication barriers, and patient-related factors. The study will run for 10 months.