Kilmarnock

Sepsis results from overwhelming reactions to microbial infections where the immune system initiates dysregulated responses that lead to remote organ dysfunction, shock and ultimately death. Sepsis remains a significant global issue - as well as direct mortality, survivors suffer long term reductions in patient centred outcomes, with reduced quality of life and functional status. Patients with hypotension and organ hypoperfusion as a result of sepsis have poorer outcomes by dysregulated inflammation, endothelial dysfunction, immune suppression, and organ dysfunction. Current guidelines highlight the importance of early fluid resuscitation, but the association of early fluid therapy with improved outcomes is unclear. In the resuscitation phase, current practice is to give intravenous (IV) fluid and intermittent vasopressor boluses if required, before, for some patients, continuous vasopressor infusion via a central venous line in Intensive Care (ICU). An alternative, early continuous peripheral vasopressor infusion (PVI) is not routine practice in the UK. Current practice in the UK is guided by NICE Sepsis guidance and the international Surviving Sepsis Campaign (SSC) consensus recommendations. Both specify intravenous fluid administration as a central tenet of early resuscitation of patients with septic shock, with intravenous vasopressor administration recommended after intravenous fluid resuscitation. NICE recommend boluses of 500ml of crystalloid and "refer to critical care for review of management including need for central venous access and initiation of vasopressors". SSC recommend 30ml/kg crystalloid in first hour, followed by vasopressors to maintain MAP\>65. The current NICE fluid resuscitation guideline, November 2020, continues to emphasise 500ml boluses of crystalloid as usual care. A recent international survey of 100 critical care and EM physicians regarding intravenous fluid resuscitation practice, confirmed that an initial bolus of 1000ml of crystalloid, followed by 500ml boluses of crystalloid remained the most common management strategy for the initial treatment of septic shock. This persisted despite the lack of benefit demonstrated in three landmark trials of protocolised sepsis management. In recent years, there has been increasing acceptance of peripheral administration of norepinephrine, based on evidence of safety and efficacy. The Intensive Care Society published guidance on peripheral vasopressor infusion in November 2020. We have recently conducted a survey amongst ED and ICU clinicians in the UK regarding attitudes and current practice related to the use of intravenous peripheral vasopressors. Eighty two respondents provided the following answers 1. Experience of use of any intravenous vasopressor in ED was high (81%); 2. Exclusive PVI made up 23% of all vasopressor use in ED; 3. Norepinephrine (norepinephrine) was the most common vasopressor (54%); 4. Barriers to PVI were local protocols and an appropriate level of care in the destination ward for a patient on vasopressor infusion.

The primary objective of Enroll-HD is to develop a comprehensive repository of prospective and systematically collected clinical research data (demography, clinical features, family history, genetic characteristics) and biological specimens (blood) from individuals with manifest HD, unaffected individuals known to carry the HD mutation or at risk of carrying the HD mutation, and control research participants (e.g., spouses, siblings or offspring of HD mutation carriers known not to carry the HD mutation). Enroll-HD is conceived as a broad-based and long-term project to maximize the efficiencies of non-clinical research and participation in clinical research. With more than 150 active clinical sites in 23 countries, Enroll-HD is now the largest HD database available and is accessible to any interested researcher - visit www.enroll-hd.org/for-researchers/access-data/ to learn more.

The purpose of this European, multicentric, prospective, non-interventional study is to document and evaluate the efficacy and safety of the treatment of severely infected patients with intravenously administered fosfomycin, including patients with osteomyelitis, complicated urinary tract infection, nosocomial lower respiratory tract infection, bacterial meningitis/central nervous system infection, bacteraemia/sepsis, skin and soft tissue infection, endocarditis or other infections, each as far as covered by the respective nationally relevant SmPC.

This trial will examine if maridebart cafraglutide as an adjunct to standard of care will lead to a reduction in heart failure (HF) events such as HF hospitalizations and urgent HF visits, cardiovascular (CV) deaths and improvement in HF symptoms in participants with HF with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF) who are obese. This is a phase 3, global, multicenter, 2-part trial with a double-blind period and an open-label extension (OLE). The trial is event-driven, and Part 1 will conclude when approximately 850 primary endpoint events have occurred.

Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA. Disease under investigation: Breast Cancer Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy. Trial Design: Open label, randomised, 3-stage Phase II/III Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm). Non Investigational Medicinal Products: Prophylactic granulocyte-colony stimulating factor (G-CSF) to be given as per local practice and 3 cycles of anthracyclines as per local practice. Treatment period: A minimum of 21 weeks of chemotherapy followed by surgery. Procedures: Screening \& enrolment Eligible patients with early breast cancer will be registered and consented for screening: BRCA mutation test Tumour Infiltrating Lymphocytes(TILs) score Cytokeratin 5/6 (CK5/6), Epidermal Growth Factor Receptor (EGFR) +/-, Androgen Receptor (AR) status by Immunohistochemistry (IHC). Standard assessment prior to chemotherapy Standard staging to exclude metastatic disease. When eligibility is confirmed, patients will be randomised via a web-based central system which will allocate each patient a unique randomisation number associated with one of the treatment arms. PARTNERing Pathway - For those patients who still have residual disease after receiving neoadjuvant chemotherapy +/- olaparib there is the opportunity to be screened to a sub-study to receive a further two cycles of chemotherapy consisting of Duralumab and AZD6738. End of Trial: For patients, the end of trial is after the last follow-up visit or contact with the research team planned 10 years after surgery. Procedures for safety monitoring during trial: Pharmacovigilance will be performed by the PARTNER Trial Office. Also, the Trial Management Group and the Independent Data and Safety Monitoring Committee will regularly review the patient safety data. Criteria for discontinuation of trial treatment on safety grounds: Severe toxicity or inter-current illness, requiring cessation in the judgement of patient's clinician. Patient within 4 weeks has not recovered from toxicity to an extent that allows further treatment. Patient unable to comply with trial procedures. Disease progression while on trial treatment. Patient becomes pregnant.

This is a major pragmatic multi-centre prospective parallel group open RCT. It will be conducted in the UK, Australia and New Zealand, funding is being sought in several countries to expand recruitment internationally. The study is in 2 phases: the vanguard and main phase. Therefore the study will run an internal pilot to prove recruitment of the relevant number of participants during the initial 2 years. The over-arching aim is to determine whether early AVR results in better clinical outcomes and cost-effectiveness than a strategy of expectant management in asymptomatic patients with severe AS. The primary hypothesis is that early AVR or TAVI in asymptomatic patients with severe AS will result in a reduction in the composite primary outcome of cardiovascular (CV) death and hospitalisation for heart failure (HHF) when compared to the conventional approach of expectant management. Potential participants will be identified by a member of the clinical care team following diagnosis with severe AS. Participants will be screened for eligibility using pre-specified inclusion/exclusion criteria. Eligible participants will be provided with a written version of the participant information sheet detailing the exact nature of the study, what it will involve for the participant and any risks involved with taking part. Participants will be given at least 24 hours to consider the information and decide whether or not to take part. The study will randomise up to 2844 patients with severe asymptomatic AS to either allocated expectant management OR aortic valve replacement. Participants randomised to AVR will be placed on a waiting list with the aim that surgery will be performed within 3 months, dependent on local hospitals' waiting lists. Participants randomised to AVR will undergo routine tests/procedures which may include coronary angiography. If the outcome of the coronary angiography reveals coronary heart disease, the decision to perform CABG or PCI will be made by the responsible cardiac surgeon and cardiologist, in consultation with the patient. All analyses will be undertaken using the principles of intention-to-treat with participants analysed in the group they were randomised regardless of treatment received. EASY-AS is collaborating with the EVoLVeD study (Early Valve Replacement guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis, Clinical Trials.gov NCT03094143). In centres where both EASY-AS and EVoLVeD are running, participants in EASY-AS will be offered the opportunity to take part in EVoLVeD. Funding has been granted by the British Heart Foundation (UK), Medical Research Future Fund (Aus) and Heart Foundation (NZ). The UK sponsor is the University of Leicester. Additional support and resources for the study will be provided by the participating Trusts and their corresponding Clinical Research Networks in the UK. The central co-ordination centre is the University of Leicester Clinical Trials Unit.

Study design: Randomised, controlled, multi-centre, open-label, phase III trial (with a single intervention registration phase). Primary Objectives The primary objectives of this study are to determine: * The impact on Depth of Response (DoR: less than VGPR versus VGPR or better) when salvage ASCT conditioning is augmented by the addition of a proteasome inhibitor * The influence of a consolidation and maintenance strategy on the Durability of Response (DuR:PFS) Secondary objectives The secondary objectives of this study are to determine: * Overall survival * Time to disease progression * The overall response rate following ixazomib, thalidomide and dexamethasone (ITD) re-induction * Time to next treatment * Progression-free survival 2 (PFS2) * Duration of response * Minimal Residual Disease (MRD) negative rate post re-induction, post-ASCT and conversion after ITD consolidation * Engraftment kinetics * Toxicity and safety * Quality of life (QoL) Participant population (refer to protocol section 9 for a full list of eligibility criteria). * Relapsed MM (with measurable disease by IMWG criteria) previously treated with ASCT * First progressive disease (PD) at least 12 months since first ASCT, requiring therapy. * ECOG Performance Status 0-2 * Aged at least 18 years * Adequate full blood count and renal, hepatobiliary, pulmonary and cardiac function * Written informed consent Interventions: All participants will be registered at trial entry and will receive re-induction therapy with 4-6, 28-day cycles of ixazomib, thalidomide and dexamethasone (ITD), in order to reach maximum response. Participants who achieve at least stable disease (SD) will be randomised on a 1:1 basis to receive either conventional ASCT (ASCTCon), using melphalan, or augmented ASCT (ASCTAug), using melphalan with ixazomib. All participants achieving or maintaining a minimal response (MR) or better following trial ASCT will undergo a second randomisation to consolidation and maintenance or no further treatment. Participants randomised to consolidation and maintenance will receive treatment as follows: consolidation with 2 cycles of ITD and maintenance with ixazomib until disease progression. Number of participants: 406 participants will be registered into the trial to allow 284 participants to be randomised at the first randomisation (R1) and 248 participants to be randomised at the second randomisation (R2).