Piła, Poland

A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB)

Supported Rescue Packs Post-discharge in Chronic Obstructive Pulmonary Disease

What is the problem being addressed? Chronic obstructive pulmonary disease (COPD) is a common lung condition in the United Kingdom, with a prevalence of 4.5% in population ≥40 years and rising4. In addition to daily symptoms such as cough and breathlessness that limit physical activity, people living with COPD are prone to unpredictable deteriorations in their health called 'exacerbations'. Exacerbations are sometimes severe enough to lead to hospital admission and are often driven by infections. A systematic review of patient outcomes in COPD identified exacerbations, especially severe hospitalised exacerbations, as the aspect of COPD that patients found most difficult to live with. Prior to the pandemic there were around 115,000 admissions to hospital with COPD exacerbations per annum6 and admissions are now returning to that level. Exacerbations are more common in the winter with greater circulation of respiratory viruses, and thus the burden of hospitalised exacerbations contributes to winter National Health Service (NHS) bed pressures and cost to the NHS. The annual healthcare cost for people with moderate and severe exacerbation of COPD in England was estimated to be nearly £1 billion in 20227. A particular problem after a hospitalised COPD exacerbation is re-admission to hospital. The National Asthma and COPD Audit Programme (NACAP) has shown that the re-admission rate is 23% at 30 days and 43% at 90 days2. A systematic review conducted by the authors identified comorbidities, previous exacerbations and increased length of stay as risk factors for 30- and 90-day all-cause readmission5. There are many interventions that can reduce the risk of COPD exacerbations but these are incompletely effective8. There is also evidence to suggest that earlier intervention with standard exacerbation treatment of antibiotics and/or corticosteroids (called a 'rescue pack') can hasten recovery, with a lessened chance of hospital admission9. As part of standard NHS care2, patients with COPD should have a 'discharge bundle' implemented, although this is often poorly delivered and has not been definitively shown to impact outcomes (likely because the wrong outcomes were chosen, and the bundle was poorly implemented)10. The provision of rescue packs is not a standard component of discharge bundles but these are sometimes provided according to local service preference3. Additionally, in usual clinical practice, some patients will have been prescribed rescue packs from primary care (GP) or a community respiratory team (CRT) prior to being hospitalised with COPD. Furthermore, patients may or may not have access to rescue packs from the GP or the CRT after hospital discharge. Although rescue packs are part of NICE guidance2, the available evidence suggests they are not effective unless provided in the context of a more comprehensive management/education plan that supports patients in their appropriate use11. In practice this usually does not happen3, with evidence that a patient with COPD will receive variable or often no support; with some patients receiving rescue packs on demand without considering antimicrobial resistance, predictable side-effects from steroid overuse, or reviewing appropriateness. The investigators have pilot data that show receiving a rescue pack on hospital discharge is controversial as the hospital team is not, in general, the team that provides ongoing support to use these. There is thus recognised over- and under-use of rescue packs, associated harm from these medicines and variable provision. Providing a rescue pack, with education on how to use and support for when to use, has not been specifically tested in the high-risk 90-day period for readmission following a hospitalised exacerbation. It is the investigators' hypothesis that rescue packs on discharge in addition to a comprehensive self-supported management plan, consisting of the Asthma+Lung UK written management plan and twice weekly automated phone and or text messaging during this 90 day high risk period, will reduce readmissions by 20% compared to standard care. Why is this research important in terms of improving the health of patients and health and care services? Reducing re-admission through provision of supported rescue pack use would benefit people living with COPD and the NHS. A reduction in readmissions of 20% could save the NHS £86 million per quarter (£344 million per annum). Conversely, demonstrating that rescue packs are not effective when used in this way will address controversy about use, and reduce pressure on antimicrobial resistance and harm from over-use of oral corticosteroids. Integrated care systems are rapidly developing out-of-hospital support for people with exacerbations of COPD including digitally supported virtual wards. The proposed trial will define the role of supported rescue pack provision in the design and implementation of these programmes, enhancing their ability to reduce demands on urgent and acute care. Whether positive or negative, this trial will help to reduce the current variation in service provision by providing a definitive answer to the study question. Furthermore, preventing exacerbations of COPD have been identified as a priority by the James Lind Alliance (JLA) Priority Setting Partnership (PSP)12.

Postoperative Dietary Intake of Hip Fracture Patients

A hip fracture is one of the most serious injuries that an older adult can sustain and with the current projections from the NHS Long Term Workforce plan of an increase in >85yrs by 55% and a current estimation of over 75,000 hip fractures per year in England, Northern Ireland and Wales with a 6-8% mortality rate at 1 year, this warrants further research to improve outcomes and look at methods beyond the National Hip Fracture Database (NHFD) to ascertain what more can be done to optimise and improve this patient group. Whilst ONS supplementation is used on an ad-hoc basis for patients with a high-risk malnutrition screening score of 2 using the MUST screening method, such tools can lack sensitivity and accuracy and are also not developed to identify the development of malnutrition in-hospital. The proposed study for this protocol is an observation study of the dietary intake of older adult hip fracture patients. The study will comprise of a weighed food diary, commencing on day zero after surgery. Potential participants that will be invited will be older adult hip fracture patients (>60yrs) with a confirmed hip fracture diagnosis that requires surgical repair. The diary will consist of the researcher weighing the plate of food before and after the participant's meal as this is regarded as a more accurate measure than relying on participant recall and does not place the participant under any additional stress. The researcher will not handle any food, and plates will be placed on a digital scale. Should a food have a specified weight - for example a yoghurt, the weight on the product will be recorded. Fluid intake will be recorded according to drinks served with meals and jugs of water per day. After each meal the researcher will weigh the plate; if it is a multiple item meal (for example meat, potatoes, and vegetables), the researcher will weigh the leftover components individually to ensure the validity of the weighed food method and to achieve the highest degree of accuracy possible. The researcher will not be present nor disrupt the participant during their meal. After their meal, the researcher will ask the participant if they have had any additional snacks and observe if they have had any assistance with their meal. Data will also be obtained regarding the times of meals, the ratio of staff to patients and if any complications have developed. The aim of this study is to explore the postoperative dietary intake of older adult hip fracture patients until day three after surgery. This builds on research where data on hip fracture patients was taken in relation to diet, anthropometry, and biochemical indices during inpatient stays. Whilst the study was commenced in the second week post-surgery and compared against values at the week 1 admission as a baseline, the researchers observed a longer length of stay, drops in energy intake that coincided with a low BMI on admission and additionally, referrals for high-risk patients that were not actioned. Subsequent studies have used varied interventions to explore postoperative nutrition, however a weighed food diary has yet to be used in the immediate postoperative period, which justifies the need for this study to explore nutritional intake as accurately as possible.

"Physiological vs Right Ventricular Pacing Outcome Trial Evaluated for bradyCardia Treatment" (PROTECT-HF)

Patients entering the study will attend for implantation of a pacemaker device and be randomised to either right ventricular pacing or physiological pacing. Patients at sites participating in echo sub-study will be informed of and given opportunity to consent to echo sub-study, this will be optional to them, even if they have consented to the main study.

Long-Term Safety of Lutetium (177Lu) Vipivotide Tetraxetan in Participants With Prostate Cancer

This is a global, prospective, multi-center, long-term follow-up (LTFU) safety study of adult participants with prostate cancer that have received at least one dose of AAA617 from interventional, Phase I-IV Novartis sponsored clinical trials. There will be no study treatment administered to participants in this study. Participants will have visits every 6-8 months for monitoring of selected AEs and laboratory parameters. The study periods include a Baseline and Follow-up Period (up to 10 years after first dose of AAA617 in parent treatment study). Participants should enroll into the LTFU study after parent treatment study requirements are fulfilled (refer to the parent treatment study protocol for requirements, including any additional requirements after participant enters this LTFU safety study). The schedule of activities for this LTFU study is designed to start from date of informed consent for this LTFU study. Participants should be followed every 6 to 8 months for up to a total of 10 years starting from first dose of AAA617 in the parent treatment study. Participants entering the LTFU study will have already completed a variable portion of the required 10-year follow-up within the parent treatment study. The specific number of visits required in this LTFU study will depend upon the time of enrollment into this LTFU study following the first dose of AAA617 in the parent treatment study. The total number of participants to be enrolled and the duration of this LTFU study will depend upon the total number treated in the parent treatment studies and their duration.

The Impact of Comorbid Chronic Pain on Older Adults With Depression in Behavioral Activation

The BASIL + trial (Behavioral Activation in Social Isolation) is a National Institute of Health Research (NIHR) funded and approved trial sponsored by Tees, Esk and Wear Valleys NHS Foundation Trust (TEWV) and led by the University of York in the United Kingdom (UK). Behavioral Activation (BA) is a type of support that may be beneficial for individuals who suffer from social isolation and/ or depression symptoms. BA assists in the continuation or introduction of activities that are significant to patients. These exercises may be beneficial to both physical and emotional health. The BASIL+ study aims to find out if BA helps reduce or prevent depression and loneliness in older adults who have ongoing health conditions during isolation in the pandemic due to COVID-19. Chronic pain affects approximately 50-60% of UK older adults and often coexists with depression. This comorbid indication affects approximately 13% of older adults. The literature on the impact of pain on depression outcomes has been steadily rising. Patients who suffer from depression with comorbid pain report significantly lower benefits, including less relief from depressive symptoms and limits the effectiveness of collaborative care for older adults with depression in the US. The collaborative care focused on antidepressant therapy and problem-solving therapy. Together, these findings suggest that pain may be a potential barrier to depression treatment response. It is unknown, however, how chronic pain impacts depression and the treatment of BA. This sub-study nested in the BASIL+ trial provides an opportunity to explore how chronic pain impacts depression and the treatment they received

Understanding Balance Impairment in COPD

Chronic obstructive pulmonary disease (COPD) is a progressive condition that affects around 1.2million people in the UK. Breathlessness is the main symptom but people with COPD are also more likely to fall than healthy people of the same age. Falling has emotional consequences, such as feelings of shame, embarrassment and fear of falling in public which leads to avoidance of outdoor activities. Researchers do not know why people with COPD fall more but they have poor balance which may, in part, be due to problems with sensory and muscle responses that would usually maintain balance. Symptoms of breathlessness and pain, plus inactivity, may further impact balance. Physical and social environments may also have a role in falls risk, but this has yet to be investigated. Pulmonary Rehabilitation (PR) which includes stamina and strength exercises, alongside education and emotional support is standard treatment for COPD but it does not include any balance exercises, meaning people with COPD who are at a greater risk of falling do not receive any routine treatment to improve balance. This study aims to investigate the physical, psychological, social and environmental factors impacting on balance in people with COPD by comparing them to older adults without COPD. The study will recruit from local hospital services (people with COPD and their carers without COPD) and within the community (healthy older adults). Balance, muscle function (size, strength and speed of nerve conduction) and physical activity will be measured, and the two groups compared. Researchers will also observe patients in their own homes and do follow up interviews to understand what it is like to live with COPD and the challenges people face. The information from this study will be used in conjunction with stakeholders to co design an intervention to improve balance in people with COPD.

Impact of Apalutamide in Metastatic Hormone Sensitive Prostate Cancer Patients

Validity of Measuring Preoperative Fitness Using Seismofit

RDC Biomarker Study

Background The proposed research will focus on Rapid Diagnostic Centres (RDCs) already established across multiple sites in England. Since 2019-2020, RDCs, have begun rolling out nationally across all cancer alliances. They are a single point of access for cancer diagnostics to allow personalised and rapid diagnosis of patients presenting with non-specific but concerning symptoms of cancer (NSCS). Cancer patients with NSCS typically have a longer interval in primary care to referral and have more advanced disease once a diagnosis is made, yet approximately 50% of cancer patients present with NSCS. These patients are poorly served by existing cancer referral pathways which can be circuitous when a clear pattern of symptoms is not present. The objectives of RDCs are to: - Support earlier and faster cancer diagnosis - Create increased capacity through more efficient diagnostic pathways - Deliver a better, personalised diagnostic experience for patients - Reduce unwarranted variation in referral for, access to and in the reliability of relevant diagnostic tests RDCs Limitations Although patients seen in RDCs are presumed to receive faster diagnosis and treatment, there is still very little known about how their vague symptoms developed over time and how these are linked to underlying health conditions, diagnosis, health outcomes and RDC effectiveness. Most RDC patients will not have cancer. Therefore, accurate and rapid triage will be essential and depend upon improved methods of risk stratification and cancer detection. There is both a significant need and opportunity to integrate quantitative research into RDCs to develop and validate novel diagnostic assays, and risk scores based on this unique population of patients. These patients both represent a primary care community, but the enriched cancer prevalence within RDCs could be utilised to facilitate more efficient biomarker development. Rationale Developing pathways to streamline care in this population group is important not only due to the importance of timely detection and treatment, but most patients in these pathways both with and without cancer are more likely to be from more deprived backgrounds or prone to being less engaged with healthcare provision. The implementation specification from NHS England highlights the need for RDCs to tackle health inequalities in their roll out. This study will allow us to generate a sample set and database to examine the potential to: i) discover high risk groups in RDC populations and ii) to detect cancer-specific signals in symptom profiling data; routine clinical and imaging data; and blood and non-blood biomarker tools. The primary aims focus on using descriptive analysis, to identify the following: 1. The number and clinical traits of Benign versus Malignant Diagnoses 2. The number and clinical traits of cancer subtypes (e.g. lung vs ovarian or other cancer) The primary aims also focus on describing how the variability between participants can delineate cancer versus benign pathology using molecular; germline risk, symptom-profiling; and clinical data from each of the four main work packages, independently or in combination using AI-based multi-parametric analysis of these traits: Descriptive analyses will provide feasibility data to develop and validate models using i) Peripheral blood and non-blood (e.g. breath and saliva) molecular signatures that can delineate between cancer and benign pathology. ii) Patient 'symptome' signatures delineating between cancer and benign pathology. iii) Digital health record signature from routinely collected clinical electronic health record (EHR) and/or imaging data and/or the 'standard' RDC dataset that delineate between cancer and benign pathology. iv) Risk stratification tools (e.g. epidemiological and genetic/PRS) that inform risk of cancer in RDC attendees and primary care. Patient Selection Overall, we expect an initial sample size of 1000 patients that will allow several exploratory analyses and simple model development/validation (in distinct datasets) within an observational platform study design. The target recruitment will be increased by the Trial Steering Group (TSG) if new relevant assays are identified, and extended funding is secured. This is supported by previous work which suggests that 1000 patients are more than sufficient to identify candidate biomarkers for further studies, it is a pragmatic approach and is not the result of power calculations. A target goal will be for 75% of cancer cases to have histological confirmation i.e. ground truth of final diagnosis to help power diagnostic accuracy and reliability for any future use of histopathological data Patients recruited will be removed from analysis where ground truth cannot be established by the time of completion of initial investigations or a period of clinical surveillance (not to exceed 12 months of surveillance after initial diagnostic pathway completed). The local Principal Investigator (PI), or members of the delegated clinical care team at participating trusts (e.g. Consultant physicians, nurse specialists, clinical fellows or admin staff), will identify suitable patients via RDC clinic appointments, RDC multidisciplinary team (MDT) lists or by RDC service evaluations, supported where necessary by clinical informatics approaches (e.g. structured query language searches) or local research team. We estimate that each participating hospital will see approximately 20-50 new RDC patients per week, thus we expect that we could recruit large numbers of patients from a small number of RDCs. This estimation may evolve considering the number of participating sites, as well as the evolving nature of how RDCs are utilised, particularly given the impact of the COVID-19 pandemic on cancer diagnosis. Recruitment will be consecutive in the order in which patients are seen within each respective RDC. Allocation of participants to a particular sample type/assay will be pragmatic based on site geography/capability of the RDC at which the patient is recruited. Study Duration The study will end when complete outcome or surveillance data is available for all participants, or after 12 months following recruitment ± completion of clinical assessment of the last patient, whichever occurs sooner. This duration is necessary to ensure confirmation of diagnosis, or stability after discharge and therefore ground truth. It is expected that recruitment will complete within two years. Patient data and samples will be stored for a total of ten years. The ten-year duration of storage is necessary to allow us to utilise more advanced laboratory and data analysis techniques, which may become available with evolving technology. Newer approaches may require very large datasets, and this timeframe would allow for a protocol amendment for expansion of our data and further research to be performed as the field evolves. Upon completion of the study, we will establish a research database for future work and will store patient data for a total of ten years. Assessment of imaging data quality and integrity and suitability of research specimens for laboratory analysis will be contemporaneous to patient recruitment/sample receipt and ongoing thereafter. Analysis will typically be performed on patients with confirmed ground truth by biopsy or sufficient clinical surveillance if benign e.g. 12 months (see above) but scans performed after this period may be accessed if future relevant data become available. Enrolment and Consent Patient enrolment into the study will occur once consent is taken and eligibility criteria is met. A trial number will be allocated to each patient for the identification research samples. In most cases, patients will donate a blood specimen on one visit (Baseline). Where recurrent visits to the hospital for surveillance CT scans are made over a longer period, then up to 3 blood specimens will be collected in total with a minimum of 21 days between each research specimen collection or a treatment intervention. This will allow the consideration of evolution of the biomarker signal in question as a determinant of cancer presence or absence (using the logic that a given signal is likely to increase alongside tumour growth and therefore be easier to detect in comparison with samples from patients without malignancy). All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment. The patient can request that any remaining samples donated are destroyed. All members of the delegated research team will ensure that patient confidentiality is maintained in compliance with the UK Data Protection Act 2018 and General Data Protection Regulation Patient Samples, Acquisition and Processing The laboratory manual will provide further details of the collection, processing, and storage of specimens. Study Oversite A Trial Steering Group (TSG) will meet on a regular basis to provide overall study oversight and clinical or scientific steer - particularly for academic/research considerations. In addition, a Trial Management Group (TMG) will meet quarterly to discuss patient recruitment, data collection, data management, data analysis, reporting for adverse events, and change management. The minutes of these meetings will be made available, and a rolling agenda will highlight any ongoing actions or concerns. In addition, the trial management team will provide day-to-day support for trial administration, including all rules and regulations concerning research studies in the UK. This includes: UK Policy Framework for Health and Social Care Research, Data Protection Act 2018 and UK General Data Protection Regulations Data Analysis and Statistical Considerations Statistical guidance and study design oversight will be provided by RM-ICR guided by the CI and Lead Statistician/Data Scientist and will be undertaken in partnership with academic partner institutions named in the protocol ± support from other academic centres. Data sharing agreements will be in place in each case. A full Data Analysis Plan will be assembled and ratified by the Trial Steering Group at its creation and on any subsequent amendment. Clinical Data analysis The main analysis, including clinical data values, will be descriptive and will be focused to inform future prospective studies. For continuous variables, the mean and standard deviation will be presented, together with the mean between-group difference, and 95% confidence interval. For binary outcomes, the percentage and frequency of patients in the outcome category of interest will be presented. When necessary intracluster correlation coefficients will be reported, together with 95% confidence interval. Where appropriate p-values will be presented. Baseline characteristics, collected at the time of commencing the study will provide an overview of the study population, both at the RDC and site level. It is expected that patients may differ based on which RDC they are recruited at and described with summary statistics including the index of multiple deprivation score for the RDC postcode, percentage of patients with comorbidities, and the cancer type. At the individual patient level, variables can include gender, age at baseline data collection, individual Index of Multiple Deprivation (IMD) values, baseline measures of all physiological measurements, comorbidity. Baseline characteristics will be summarised as the mean, standard deviation and range for continuous, approximately symmetric variables; medians, interquartile range and range for continuous, skewed variables; frequencies/percentages of patients/RDC in each category for categorical variables. Laboratory Data Analysis Analysis of laboratory data will lie in the first instance with the clinical and scientific lead for each work package with further details provided in the laboratory manual and local laboratory protocols. The assays will give a read out for each patient that will be assessed using receiver operating characteristic curve analysis against each endpoint. Firstly, this will be performed using a single biological parameter for cancer versus non-cancer, or most likely cancer subtype, and then in combination with other laboratory and clinical endpoints as a multiparametric signature for the same endpoints as outlined in the protocol.