Basildon

There is an evolving crisis of chronic liver disease (CLD) in the UK and it is the only major chronic disease which is on the rise. The advanced stages of CLD, known as cirrhosis (a hardening and scarring of the liver), is the third biggest cause of death and loss of working life years behind heart disease and self-harm. People die from cirrhosis young with more than 1 in 10 in their 40s. Patients with cirrhosis are very susceptible to infections, antibiotics become ineffective and patients may become infected with 'super bugs'. There is an urgent need for antibiotic-free approaches. The body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. Many of these bacteria live within our bowel and help our immune system fight infection. There are increased numbers of 'unfriendly' bowel bacteria in patients with cirrhosis which emit substances that are harmful to health and disrupt the immune system. It could be beneficial to replace the unfriendly bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant (known as faecal microbiota transplantation or FMT). The PROFIT trial was recently performed as a preliminary trial of FMT which was placed into the bowel with the help of a flexible camera (endoscopy). The study showed FMT was safe with no serious side effects, but patients told us they would prefer to take tablets rather than have an endoscopy. The chief investigator and her team have therefore made a capsule which contains dried stool from a healthy donor. Participants will need to take 5 of these capsules to achieve the same dose. The PROMISE clinical trial is to test whether treating patients with FMT capsules will reduce the likelihood of them getting an infection by measuring the time it takes to develop an infection resulting in hospital admission. This will be compared to a 'dummy' capsule that contains no FMT (placebo). Patients will be selected at random to have FMT treatment or placebo and both the study team and the patients will not know which treatment they are taking. Participants will need to take 5 capsules every 3-months. Participants will continue treatment for a total of 21-months or until they develop their first infection leading to hospital admission and will be followed-up for a maximum of 2-years. This study will also examine if having FMT will reduce the side effects of cirrhosis and if it has beneficial effects on the liver and immune system. The investigator team will study whether it reduces hospital admissions, the incidence of 'super-bug' infections and death. Laboratory studies will look at whether FMT treatment will help the immune system fight infection. The World Health Organisation describes the resistance of bacteria to the effects of antibiotics as one of the biggest threats to global health. The discovery of new antibiotics has not kept pace. The government's white paper proposes a 5-year plan to tackle resistance to antibiotics. Consultation with our patient co-applicant, patient advisory group, The British Liver Trust and Guts UK Charity have highlighted recurrent hospitalisation, over-use of antibiotics and fear of acquiring a 'super-bug' as being important priorities to patients. The results and study findings will be published in conjunction with patient support groups, the wider media and the NHS. The investigator will ensure the research impacts on the management of patients with CLD and shapes policy and guideline development.

This study will be done to see if ziltivekimab can be used to treat people living with heart failure and inflammation. Participants will either get ziltivekimab or placebo. Participants will get study medicine for once-monthly injections either in a pre-filled syringe to inject the study medicine into a skinfold or a pen-injector to inject the study medicine into flat skin. The study is expected to last for up to 4 years. Participants will have up to 20 clinic visits. Participants will have to use a study app on their phone to record and share information about all their injections of study medicine and to fill in questionnaires.

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.

SCIENTIFIC RATIONALE Heart failure (HF) is a global health challenge affecting over 64 million people, with rising prevalence. Managing HF effectively is crucial to improving outcomes, but assessing and managing fluid status remains a significant challenge. Fluid congestion is a common cause of symptoms and hospitalizations for acute decompensated heart failure (ADHF). National audits indicate many patients are discharged before achieving adequate decongestion, increasing the risk of readmission and worsening prognosis. Traditional methods, such as physical exams and imaging, correlate poorly with congestion. Conditions like obesity (BMI \>30) and kidney disease further reduce the accuracy of diagnostic tools, including echocardiography and biomarkers like NT-proBNP. Hospitalizations for decompensated HF are associated with worse prognosis, progressive cardiac dysfunction, and higher mortality, highlighting the need for improved in-hospital management and prevention of readmissions. Bioimpedance Analysis (BIA) is a promising non-invasive tool that measures body composition and fluid distribution, providing insights into total, intra-, and extracellular water. BIA is inexpensive, portable, and reproducible, making it suitable for regular clinical use. Studies suggest BIA-guided therapy may improve fluid management and reduce NT-proBNP levels, potentially enhancing outcomes. This study aims to evaluate BIA's effectiveness in guiding fluid management in hospitalized HF patients with worsening symptoms. By enabling precise fluid assessment, BIA could optimize diuretic therapy and improve patient outcomes. PRIMARY RESEARCH OBJECTIVE The principal research objective is to determine if BIA guided management of heart failure inpatients, compared to usual standard of care, results in a reduction in heart failure events within 90 days post discharge. A heart failure event is defined as an outpatient requirement to increase oral diuretics or hospitalization for intravenous diuretics, due to decompensated heart. SECONDARY RESEARCH OBJECTIVE The secondary objectives are to determine if BIA guided management of heart failure inpatients, compared to usual standard of care, results in: 1. A higher rate of Acute Kidney Injury (defined by serum creatinine increase by (defined \>=1.5 and \<2 fold increase from baseline at any time) 2. A longer hospital Length of Stay including within a virtual ward. 3. A reduction in NTproBNP at 2-4 weeks after discharge from hospital. 4. An improvement in Patient Reported Outcomes (KCCQ-12), 2-4 weeks after discharge from hospital. 5. A lower rate of heart failure related events within 3, 6 months and 12 months. 6. A lower rate of All-cause mortality at 12 months STUDY DESIGN This study is a single-centre, single-blinded, randomized controlled trial designed to evaluate the effectiveness of bioimpedance analysis (BIA) in guiding fluid management in patients who are hospitalized with acute decompensated heart failure (ADHF). The study aims to compare the outcomes of BIA-guided therapy versus standard care in terms of fluid management and HF-related outcomes. PATIENT COHORT Eligible participants would include patients hospitalized for the management of Acute Decompensated Heart failure (ADHF), at Basildon and Thurrock University Hospital. All patients would be enrolled in the outpatients heart failure disease management programme. Consent Potential participants will be identified and screened by the direct clinical team. If patients fulfil the eligibility criteria they will be approached by a member of their clinical care team. The clinical team will briefly explain the study and provide the patient with an ethically approved patient information sheet. This document will outline the details of the study, including its purpose, what participation involves, and how the patient's information would be used. The potential participants would be offered at least 24 hours to review the information and will have the opportunity to ask questions and consider whether they are interested in participating. This approach ensures that potential participants are introduced to the study by trusted healthcare professionals with whom they already have a clinical relationship. If the patient expresses interest and agrees, the research team can follow up to obtain formal consent and enrol the patient in the study. The original consent form will be retained in the site file, a copy provided to the patient and a copy inserted into the patient medical notes. Randomization Participants provide consent will be randomized sequentially, in a 1:1 ratio using an online random number generator with an upper limit of 255, to either the BIA-guided therapy group or the standard care group. Odd-numbered patients will be assigned to the BIA-guided group (Group 1), and even-numbered patients will be assigned to the standard care group (Group 2). Interventions BIA-Guided Group Bioimpedance Analysis (BIA) will be performed within 24 hours of admission using the portable Bioscan touch i8 device (Maltron International, Essex, UK). BIA measurements will include total body water (TBW), intracellular water (ICW), extracellular water (ECW), and the derived parameter "dry weight". Results are available at the bedside within 2 minutes. A member of the research team not involved in the patient's care will conduct the BIA and record the estimated dry weight in the patient's medical record. Diuretic therapy and other fluid management strategies will be adjusted based on the BIA estimated dry weight, in addition to standard clinical assessments, including physical examination, patient symptoms, and conventional diagnostic tools (e.g., chest X-ray, echocardiography), to achieve euvolaemia. BIA will also be performed at discharge for comparison to baseline results. Standard Care Group A member of the research team not involved in the patient's care will conduct the BIA and will record the estimated dry weight in the research records at 24 hours of admission and at discharge. These results would be blinded to clinicians managing the patient, who will aim to achieve euvolemia based on usual clinical judgement, discretion and conventional diagnostic tools. FOLLOW-UP All patients will be followed up in line with NICE guidelines for these patients, at 2-4 weeks post discharge. This will be conducted based on standard clinical assessments along with usual blood tests, to include NTproBNP. Furthermore, patients will be administered a quality-of-life questionnaire; Kansas City Cardiomyopathy Questionnaire (KCCQ-12); which is validated to assess symptoms, physical and social limitations, and quality of life in patients with heart failure, with respect to the preceding 2 weeks. Any additional contact with patients will be in line with routine clinical requirements. Outcomes will be recorded at pre-specified secondary endpoints. SAMPLE SIZE CALCULATION 30-180-day readmission for heart failure is reported between 10-25%. The investigators have determined that a sample size of 232 (116 for each group) provides a two-sided 95% confidence interval for the difference in the event proportions with a width that is equal to 0.2. This provides a reasonable estimate of clinical significance for this pilot study when the estimated event proportion for the control group is 20% and 10% for the intervention group. The sample size was increased to 255 (an added 10%) to allow for some loss of information due to early study discontinuation. DATA MANAGEMENT The data would be collected in an anonymized fashion and would be collated along with baseline demographic data as part of each hospital episode. The data would be analysed after 220 consecutive hospitalized patients have been entered into the study and each patient has been followed up for a minimum of 12 months. STATISTICAL ANALYSES Statistical analyses would be performed using commercial software. A statistical significance level of 0.05 will be used. Discrete variables would be expressed as n (%) and continuous variables as mean (SD) or median (interquartile range \[IQR\]). Comparisons between survivors and non-survivors will be done with the use of chi-square test and Fisher exact test for categoric variables and t test for continuous variables if normally distributed or Mann-Whitney test if not normally distributed. The Spearman rank correlation would used to perform correlation analyses. All hypothesis testing will be 2 tailed. Cumulative incidences will be analysed by the method of Kaplan-Meier and compared using the log-rank test. In addition, the relationship between several clinical variables would be tested in a multivariate Cox model to predict long- term mortality and this will be described with hazard ratios (HR) and 95% Confidence Intervals.

Giant cell arteritis (GCA), also known as temporal arteritis, is the most common form of primary systemic vasculitis, with up to 75,000 cases a year identified in the EU and US. It occurs almost exclusively in people over the age of 50 years and is considered to be a medical emergency. If not treated with high-dose glucocorticoids immediately, the thickening of the inflamed blood vessel wall can cause irreversible visual loss or stroke. GCA can lead to significant morbidity across a variety of systems, due to both the disease, and complications of treatment. Diagnosis may be confirmed with a temporal artery biopsy, imaging (e.g. USS/CT/MRA/PET-CR) or based on clinical signs (e.g. erythrocyte sedimentation rate) and symptoms (e.g. a new headache, jaw claudication, visual disturbances, temporal artery abnormality such as tenderness or decreased pulsation) . Polymyalgia rheumatica (PMR) is characterised by inflammatory limb-girdle pain with early morning stiffness, and a systemic inflammatory response demonstrated by elevated inflammatory markers. The UK GCA Consortium is a multi-centre observational study, the main arms of which recruit prospective (participants with suspected GCA) and retrospective cohorts (participants with confirmed GCA diagnosis). Analysis of data collected on these cohorts will help achieve the primary aim of finding genetic determinants of GCA and PMR susceptibility, in order to yield novel insights into disease pathogenesis. Secondary aims, and their associated analyses, are as follows: * Phenotype: characterising GCA and PMR subtypes, based on clinical features; imaging; cells; subcellular fractions and molecules in the circulation and/or arterial tissue; genetic/epigenetic/transcriptomic/proteomic or metabolomics factors, including next generation sequencing (whole exome sequencing) of selected cases. * Life impact: determining what aspects of the disease and treatments affect patients' quality of life, as assessed by patient-reported outcomes. * Long-term outcomes: characterising prognosis of GCA and PMR - both effects of the disease and its treatment - by longitudinal follow-up through electronic linkage to health records. * Exploratory analyses: exploring the potential role of environmental factors and co-morbidities on phenotype and outcomes. * Diagnosis, prognosis: improving diagnosis of GCA and PMR, and identifying factors that predict diagnosis, such as diagnostic clinical features, and prognostic and diagnostic biomarkers. * Disease activity: monitoring participants who commence a synthetic or biological disease-modifying anti-rheumatic drug (s/bDMARD). Finding a biomarker for GCA and PMR disease activity, which might be clinically useful in helping to optimise steroid and s/bDMARD treatments for individual patients.

All patients will be included just after implantation and will then be followed during 48 months after inclusion. At each on-site or remote follow-up visit (1 to 3 months, 6, 12, 24 and 48 months), performances of the remote monitoring functions and the cardiac pacing system itself will be measured, and safety will be monitored during the whole clinical investigation duration.

Atrial fibrillation (AF) increases the severity of, and death from, heart failure (HF). Several small studies have demonstrated that restoration of sinus rhythm by catheter ablation in patients with HF improves left ventricular (LV) function and exercise tolerance. What is unknown is whether or not AF ablation reduces all-cause death and urgent CV hospitalisations in populations with HF. The current trial will answer this outstanding question, which is faced by HF clinicians and electrophysiologists on a daily basis. AF ablation can be performed very effectively and efficiently using a cryo-balloon or radio-frequency ablation PVI technique. These techniques have evolved slowly and are unlikely to change substantially over the course of this trial. One small trial (n=363) in implantable cardioverter-defibrillator and CRT defibrillator recipients (CASTLE-AF) reported a death benefit of AF ablation but the patients were highly selected and the death reduction was far higher than real world expected differences. Recent studies have noted that the population randomised in CASTLE-AF was not representative of the general HF population with only 7% of patients in the "real world" setting meeting the trial entry criteria. CASTLE-AF is therefore provocative but inconclusive; it has made little change to clinical practice. As no studies have investigated the death benefit in a general HF population, the proposed trial is necessary and warranted. This study is designed as a randomised, open label multicentre clinical trial in which catheter ablation and medical therapy is compared to medical therapy alone in patients with HF with reduced ejection fraction (\<50%) and paroxysmal or persistent AF to determine if this reduces all-cause death and urgent CV hospitalisations as well as improving QoL. By utilising the clinical and research networks of the British Heart Failure Society and British Heart Rhythm Society (BHRS) we will recruit 1200 patients. The current trial will be almost three times the size of the only previous inconclusive trial which was reported in the New England Journal of Medicine.

This study is open to adults with chronic kidney disease at risk of progression. People with and without type 2 diabetes can take part in this study. The study is open to people who take other medicines called angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). People who already take empagliflozin or any other sodium-glucose cotransporter-2 inhibitor (SGLT2i) can also join. The study is also open to people who currently do not take any of these treatments. The purpose of this study is to find out whether a medicine called BI 690517 helps people with chronic kidney disease when taken in combination with a study medicine called empagliflozin. Worsening of kidney function increases the risk for kidney failure, cardiovascular disease, and heart disease. This study has 2 parts. In the first part, participants get empagliflozin or placebo matching BI 690517 for at least 6 weeks. Participants continue taking ACEi or ARB throughout the study if such treatments are indicated. In the second part, participants are divided into 2 groups by chance. One group takes BI 690517 tablets and the other group takes placebo tablets. Placebo tablets look like BI 690517 tablets but do not contain any medicine. Participants take 1 tablet once a day in addition to empagliflozin for the duration of the study. The doctors document when participants experience worsening of their kidney disease, go to hospital due to heart failure, or die of cardiovascular problems during the study. The time to these events is compared between the 2 treatment groups to see whether the treatment works. The study continues until the required number of events have occurred which is about 3 to 4 years. During this time, participants visit the study site about 4 times within the first 6 months. Then they visit the study site every 6 months. At the visits, doctors regularly check participants' health, take blood and urine samples, measure blood pressure and weight, check kidney function, and take note of any unwanted effects.

The COSIRA-II study is a multicenter, randomized (1:1 ratio), double-blinded, sham-controlled clinical trial.

The Shockwave Javelin Coronary IVL Catheter was developed to address the current challenges clinicians face when treating tight, difficult to cross, calcified coronary lesions and was designed as a rapid exchange catheter to deliver intravascular lithotripsy to those complex lesions in the coronary vasculature. The intended benefit of the Shockwave Javelin Coronary IVL Catheter is to allow the catheter to modify calcium in tight, difficult to cross lesions to increase the compliance of the vessel and allow further crossing of the device or additional treatment at the discretion of the physician. Up to 158 subjects (150 evaluable) subjects with moderate-to severely calcified, stenotic de novo coronary artery lesions presenting with stable angina or following stabilization after acute coronary syndrome (ACS) that are suitable for non-emergent percutaneous coronary intervention (PCI) will be enrolled at up to 35 sites. Once the pivotal cohort is fully enrolled (N=158), the study will continue to enroll an Extended Investigation cohort of up to 250 additional subjects.