Llandough

This trial will include 378 participants with active CD, defined as an HBI \> 6 and the presence of endoscopic ulceration. Approximately 50% of the enrolled population will be bio-naïve and 50% exposed to no more than 1 prior biologic. Eligible participants will be randomised 1:1 to either epigenome-guided treatment selection or usual SOC treatment selection. Randomization will be stratified by prior biologic use (yes/no) and corticosteroid use (yes/no) at baseline. Blood samples for the assessment will be collected for all participants during screening. Peripheral blood will be tested via a machine-learning-powered epigenetic biomarker assay. EpiPredict is a software designed for CSV file input, data transfer, storage, and display, and will be serving as a EpiPredict clinical decision support system. It recommends treatment selections for 2 biologics (Vedolizumab (VDZ) and Vedolizumab (UST)) for CD utilizing genetic data. The intervention (EpiPredict software) will indicate the probability of response to both VDZ and UST (though sites will only be provided with the treatment with the highest outcome) for the treatment of CD using a hybrid capture-based methylation assay (approved for research use only) and the EpiPredict software. All participants in the study will be administered their biologic therapy in accordance with the product label and local SOC recommendations. Dose adjustments will be allowed in both groups at the treating investigator's discretion. During the 26-week treatment period, the study assessments will follow the SOC regimen of the assigned biologic treatment. For participants receiving VDZ, study assessments are to occur at Weeks 6, 14, and 26; for participants receiving UST, study assessments are to occur at Weeks 8, 16, and 26. Long-term follow up assessments are to occur every 6 months (Months 12, 18, and 24) after Week 26. Data for long-term follow up assessments will be collected from the participant's medical records captured at routine SOC visits and online questionnaires.

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.