Warminster, United Kingdom

Validation of Heart Rate Recovery as a Peri-operative Risk Measure

There are approximately 1.5 million major operations carried out in the NHS every year. As the population ages, and surgical technique becomes more advanced, more patients are undergoing operations which carry a high risk of complications. Currently, doctors predict this risk by asking patients about medical problems and their level of physical fitness. If an operation is very high risk, a patient may undergo cardiopulmonary exercise testing (CPET) where the patient rides an exercise bike to maximum effort (exhaustion) whilst their heart and lung function is measured. This gives the doctor specific numbers which can be discussed with the patient about the risk of complications after surgery. However, CPET is expensive and not all patients are able to do it, for example due to joint or circulation problems. Patients can also find attempting to reach maximal effort demanding and uncomfortable. Heart rate recovery (HRR) after maximal exercise has been shown to indicate post-operative risk of complications, and is also related to life-expectancy in people with heart failure. The utility of HRR after submaximal exercise however has not been investigated as extensively. One group demonstrated that submaximal HRR predicts post-operative complications after lung surgery, and submaximal HRR also predicts life-expectancy in healthy individuals. There is less information about submaximal HRR as the methods of measuring it are not standardised. Previous work by our group has confirmed the reproducibility of submaximal HRR in a healthy population, and demonstrated different ways in which to measure it. We believe that submaximal HRR provides a "middle-ground" method of assessing how fit a patient is for surgery. With informed consent, 95 patients across four hospitals in the West of Scotland will perform a step test pre-operatively. The step test will involve non-invasive measurement of the heart rate. Patients will exercise until approximately two-thirds of their predicted maximum heart rate is reached and then recover sitting, whilst the rate of their heart rate recovery is recorded. Patients will have pre- and post-operative troponin values measured (blood marker of strain/injury to the heart). Alongside the blood tests, patients will also answer questionnaires related to their quality of life, and information regarding other post-operative complications will be recorded. Our study aims to demonstrate that submaximal HRR is predictive of post-operative myocardial injury (stress/injury to the heart wall due to the body's response to the operation) and that is it a valid measure when compared to the scores, blood tests and exercise tests that are currently in use in the NHS. In the future, submaximal exercise testing with HRR measurement may be offered to patients unable to perform CPET and will guide shared decision-making between patient, surgeon and anaesthetist to ensure the best outcome for the patient regarding their surgical options.

Phase Ib/IIa Trial With AC01 in Patients With HFrEF

During the dose escalation phase, patients will be given AC01 orally twice daily for seven days. In the cohort expansion phase, patients will be given AC01 orally twice daily for 28 days at dose levels selected on the basis of results of the dose escalation phase.

A Trial That Evaluates Disease Characteristics in Hemophilia B Adult Male Participants Receiving Prophylaxis With Standard of Care Factor IX Protein (FIX) Replacement Therapy

Longitudinal Sample Collection to Investigate Adaptation and Evolution of Ovarian High-grade Serous Carcinoma

BriTROC-2 is a sample collection study from women with ovarian cancer from the point of diagnosis to the time of disease relapse. Ovarian cancer has a poor prognosis. The large majority of patients with ovarian cancer will relapse and ultimately develop fatal chemotherapy resistance. Although there is a wealth of information regarding the molecular basis of ovarian cancer at diagnosis, very little is known about the drivers of treatment resistance (both intrinsic and acquired) and the processes that are active at relapse. This research requires sequential collection of tumour material for women throughout the course of their disease. This multicentre study will collect tumour samples, ascites (fluid within the abdomen) and blood from women with newly diagnosed ovarian cancer and follow these women through to relapse of their disease. The samples collected will be used to look at patterns within the tumour to identify those that are able to predict response to chemotherapy and outcome. Assays and models will be developed that can look at the process that are active in a tumour at time of sample acquisition. This will give clues into the mechanisms that drive treatment resistance. Ultimately this research aims to guide future treatment options for women with ovarian cancer. Recruitment will be over 3 years and this study will be conducted at sites with expertise in managing ovarian cancer and the ability to carry out the appropriate sample collection and collect high quality clinical data. This study is the second collaborative project within the UK to collect samples from women with ovarian cancer. The success of the first study, BriTROC-1, demonstrated the feasibility of sample collection from women with relapsed ovarian cancer. The methods and frameworks established in BriTROC-1 will be used for BriTROC-2.

The Role of Circulating Tumour DNA in Head and Neck Cancer

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasingly prevalent cancer type in Scotland, with an annual incidence rate of 23.4 per 100,000 of population in 2017 compared to 17.3 per 100,000 in 1993 [1]. This is due in part to an increased frequency of human papillomavirus (HPV) -related disease, which accounts for >70% of cases of OPSCC, and to continuing high rates of smoking. The current standard of care in OPSCC rests on clinical assessment and cross-sectional imaging followed by biopsy with histopathological diagnosis via immunohistochemistry (IHC) and PCR testing of the tumour for HPV. Follow-up is by chemo-radiotherapy (CRT) in most cases, with interval imaging to gauge post-treatment response to therapy and salvage surgery as required [2]. HPV+ve OPSCC has a generally good prognosis after treatment with CRT (3-year survival 82%), whilst HPV-ve OPSCC has a much poorer prognosis (3-year survival 57%)[3]. Surgical access to post-treatment OPSCC for biopsy can be difficult and even with recent advances in functional imaging there are still significant numbers of patients, at first presentation and at relapse, with indeterminate results [4]. The poor prognosis of HPV-ve disease and the major differences in prognosis and management between HPV+ve and -ve disease underline the importance of accurate identification of HPV status in patients with OPSCC and emphasise the need for more reliable markers of residual or recurrent disease. The analysis of circulating tumour-derived DNA (ctDNA) from patient blood - "liquid biopsy" - represents a minimally invasive approach to cancer diagnosis and management, with the potential to transform clinical care through identification in blood ctDNA of actionable tumour-derived mutations, detection of minimal residual disease and early detection of disease recurrence [5]. There has been significant interest in developing liquid biopsy approaches in HPV+ve OPSCC, with several studies including our own indicating that real-time monitoring of HPV levels in plasma cell-free DNA (cfDNA) can accurately determine HPV status, indicate completeness of response to treatment and provide evidence of tumour recurrence earlier than routine surveillance and before symptomatic presentation [6-8] (Thomson et al 2020, MedRxiv). In HPV-ve OPSCC, a particular problem in Scotland due to high rates of smoking, no such blood-based markers are available. As well as the opportunities to validate and translate HPV cfDNA as a biomarker for remission and relapse in HPV+ve OPSCC, there is therefore a need to develop new diagnostic assays to assist clinical decision-making steps in the management of HPV-ve disease. The investigators aim to carry out liquid biopsy studies that will improve diagnostic accuracy and clinical management of Scottish OPSCC patients. In HPV+ve OPSCC, The investigators will expand our existing cohort and prospectively evaluate the clinical utility of cfDNA HPV analysis as a biomarker for routine care. In HPV-ve patients, The investigators will study the development and evolution of HPV-ve disease through combined genomic analyses of tumour DNA and circulating cfDNA, with the aim of identifying blood-based biomarkers and new targets for personalised therapy in this poor prognosis form of OPSCC. Understanding the molecular events surrounding OPSCC development and responsiveness to treatment, and identifying biomarkers for blood-based disease monitoring stand to have a significant impact on patient survival and quality of life of Scottish patients with OPSCC. The work proposed here - built upon a strong foundation of pilot data and collaboration between academia and the NHS - will directly assist clinical care and treatment efficacy for OPSCC patients in Scotland.

A Study to Explore Biomarkers in Samples of Blood, Urine, Stools, Hair Follicles and Saliva From Patients With Cancer

This is a study in patients with confirmed malignant disease (solid tumour) due to start anti-cancer therapy/radiotherapy or attending for clinical assessment. Patients will be asked to give additional blood, hair, urine or saliva samples for research compared to standard treatment in this proposal. Blood (25 mL) will be taken, once, prior to starting therapy (or at routine assessment). Further samples of 25 mL of venous blood will be taken at each subsequent visit for chemotherapy in patients who undergo chemotherapy treatment, and at fixed timepoints for those undergoing treatment with non-chemotherapy regimens. These timepoints will coincide with routine hospital visits for disease assessment purposes for these patients and no additional visits will be required. Similarly, a 20 mL sample of urine will be collected at the above timepoints from patients with urological cancers. A 2 mL sample of saliva will be collected at the above timepoints from patients with head and neck cancers. Where possible 25 mL of venous blood will also be collected at each subsequent follow-up visit after completion of chemotherapy (other systemic therapies, or radiation therapy) until there is documented disease progression. Patient treatment, supportive care and disease assessment will be unaffected by participation in this study. Collected samples will be analysed for biomarkers (proteins or DNA from tumour cells sometimes detected in a sample of blood or urine) at the Translational Pharmacology Lab, University of Glasgow. These biomarker results will be compared with patient outcome (objective response and overall survival) with the aim of developing biomarkers that might help us to better select the type of chemotherapy regimen given to individual patients. For patients with breast cancer who will be treated in the neo-adjuvant setting, they will be asked to provide 3 stool samples (prior to treatment, halfway through treatment and at the end of treatment) to study changes to gut microbiota.

A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF)

URAISE: Ultrasound Regional Anaesthesia Interpretation Skill Evaluation

This is a prospective, multi-centre study leading to the identification of a validated, reliable and defensible tool for assessing ultrasound-guided regional anaesthesia (UGRA) image interpretation. This study will have 5 Phases: Phase 1 - nerve block identification: A panel of academic experts in regional anaesthesia will review published evidence from UGRA international guidelines. They will determine which UGRA nerve blocks are relevant to anaesthetic practice in the UK, and list the anatomical and clinical knowledge that is relevant to performing these nerve blocks. Phase 2 - content and question generation: A panel of experts in regional anaesthesia, recognised for their involvement in regional anaesthesia societies and publications, will review the UGRA nerve blocks and the relevant anatomical structures identified in Phase 1. The anatomical structures that must be identified on ultrasound for the safe and effective performance of these blocks will be agreed upon following panel discussion. Each structure will be categorised as either: - Essential - Desirable - Expert - Not relevant This information will be collated by the Primary and Co-investigators to generate a pilot test of UGRA interpretation content and questions. Phase 3 - preliminary testing: The pilot test will be administered by local investigators via a computer-based application to 35-50 anaesthetic trainees and consultants, recruited by email and flyers sent to schools of anaesthesia across the UK. The cohorts will include an equal number of trainees and consultants of varying regional anaesthesia and clinical experience. The pilot test will contain short video clips and images of ultrasound guided regional anaesthesia with questions in a constructed response question (CRQ) format to identify relevant structures, anatomy and clinical knowledge, which will require the participant to write free-text responses to questions. It is important to recognise that some participants will be familiar with the CRQ format while others might be more familiar with other forms of assessment question. Participants in the pilot will therefore be provided with sample questions and answers prior to the test to familiarise themselves with the question format. "Face validity" of the test (i.e. whether it measures what it claims to) will be assessed by asking participants to comment on ease of understanding and to identify terms that appear ambiguous. Participants will be able to comment in a text box after each item in the questionnaire. They will also be asked to comment on how they would improve the test and any relevant anatomy or clinical knowledge missing from the questions. The format of the test will be amended based on the comments. A "Difficulty Index" for each item will be calculated by dividing the number of correct responses by the total number of responses. A higher value suggests a question is easier to answer. Any item with a difficulty index of < 50% will be considered too difficult to answer by the respondents and will be considered for removal. This will be compared to the information gathered from the panel of experts on test items (that is, whether the anatomical structure is essential, desirable, expert or not relevant to the specific ultrasound guided nerve block). The pilot study will be used to identify how well the answers for each test item discriminate between the participant's level of ultrasound experience ("construct validity"). Differences in ultrasound interpretation skills between study groups will be analysed using statistical modelling. Items that discriminate well will be retained and those that discriminate poorly will be removed from the main test. Reliability of the test will be improved by presenting the pilot test items in a random order to minimise the effect of cognitive fatigue diminishing performance on subsequent items. The average time taken for participants to complete each item in the pilot test will also be recorded to guide the optimal final study test length. It is important to balance the maximum number of test items whilst minimising the risk of cognitive fatigue and participant drop out. While the pilot test will necessarily have more items than the final test, pilot test participants will be asked to comment on the point at which they felt fatigued to guide this balance. It will also guide understanding of whether the level of regional anaesthesia experience affects fatiguability. Phase 4 - testing for content validity: To ensure all items in the assessment tool contain content that tests the domain the investigators intend to test, following the pilot the amended test will be presented to the panel of 5 experts in regional anaesthesia, who will be asked to rate the suitability of ultrasound images and questions to performance of the block. This will be on a 4-point Likert scale: 1. = definitely not suitable 2. = probably not suitable 3. = probably suitable 4. = definitely suitable The "content validity" (i.e. the extent to which a measure fairly represents a particular domain) will be derived by dividing the number of experts who rated the item as probably suitable and definitely suitable (3 and 4 on the scale) by the total number of experts. Items found to be appropriate by a sufficiently high percentage of participants will be selected. Phase 5: psychometric main study testing The final assessment tool will be administered to an equal number of anaesthetists of varying regional anaesthesia experience. Participants will be recruited using emails and flyers sent to schools of anaesthesia across the UK. Each participant will answer a series of demographic questions, including age, gender, handedness, as well as level of training and practical experience in UGRA to account for inconsistencies in clinical exposure at different stages of training. The exam will consist of constructed response questions (CRQs). Participants will be provided with sample questions and answers before the test to familiarise themselves with the question format. The construct validity of the tool will be tested by comparing the scores of anaesthetists with their level of experience in regional anaesthesia. The level of experience is a proxy outcome measure for their proficiency in ultrasound-guided regional anaesthesia. Differences in ultrasound interpretation skills between study groups will be analysed using statistical modelling. At the end of the assessment, there will be a short questionnaire to ascertain ease of understanding and suitability of ultrasound images to support the face validity of the test. The "internal reliability" (i.e. the consistency of results across items in a test) of the responses will be assessed using statistical modelling. A split-test method will also be used for each participant to compare the first half of their assessment with the second half to ensure internal consistency of their item responses. The difficulty index calculated for items in the pilot study will be used to ensure a balanced set of test items, in terms of their difficulty, in the first and second halves of the test. All items will be made mandatory. The test will be administered by local investigators via a web-based application. It will have an automatic system of marking to minimise inter-marker differences. It will also be manually checked by investigators who are blinded to the level and identity of the participant. The investigators will aim to recruit a minimum of 250 participants, each of whom will be allocated a participant number to maintain anonymity. The results will be analysed only when recruitment has ended.

A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 As Monotherapy and Combination Therapy in Subjects with BRAF V600 Mutant Solid Tumors

CharacterisatiON of carDiac funCTion in Intensive Care Unit Survivors of Sepsis.

Sepsis is one of the most common reasons for admission to ICU in the UK and it is well established that adverse cardiovascular events are common following sepsis. In fact, the risk of adverse cardiovascular events such as MI, Heart Failure and Stroke is in excess of 60% greater compared to those who have not had sepsis. Similarly, heart failure is one of the most common causes of readmission to hospital following an episode of sepsis. The underlying mechanisms for this phenomenon are unclear and CONDUCT-ICU investigators intend on answering this question. Investigators will collect cardiac and inflammatory biomarkers from participants at the point of discharge from ICU. Following discharge from hospital, cardiac magnetic resonance (CMR) scans of the heart will be undertaken in participants 6-10 weeks post-discharge from hospital to examine for evidence of inflammation in the heart. Further blood samples will also be collected to look for evidence of inflammation and heart muscle injury at this point in addition to patient reported outcomes measures using validated questionnaires. Participants will be identified with their direct clinical team in ICU and are nearing or at the point of discharge from ICU. If eligible for the study, they will be approached by researchers and provided them with an information sheet and written consent form. Participants will be given up to 24hrs to decide if they wish to take part in research and if so, they will sign the consent form. Participants are free to withdraw from the study at any time, without any reason given, and this would not affect the standard of care they receive. This is an observational cohort study. If willing to take part, participants will receive the normal follow-up that would be undertaken following discharge from ICU. In addition, researchers will collect a sample of blood from participants at the time of discharge from ICU and again at 6 -10 weeks post discharge. A Cardiac Magnetic Resonance (CMR) scan will be undertaken 6-10 weeks follow up. Researchers will assess the patient's day-to-day function and quality of life by asking them to complete validated questionnaires. These questionnaires should take five to ten minutes to complete and help will be available if required. Participants will complete these questionnaires at the follow-up visit 6-10 weeks following discharge from hospital with the help of the researchers conducting the study The first blood sample will be collected following discharge from ICU whilst the patient is still in hospital. Further blood samples will be collected 6-10 weeks following discharge from hospital. Blood samples for patients undergoing CMR will be taken when they attend for scan. Blood sampling for patients who do not undergo CMR imaging will attend for a separate follow-up visit for collection of samples. Patients are normally invited to attend ICU follow-up via the InS:PIRE service at approximately 6-10 weeks post-discharge. Where possible researchers will combine blood sample analysis with routine follow-up visits in clinic to which participants would normally be invited. If they are not able to attend follow-up and are not attending for CMR scan, then researchers will invite them to the research facility within the local sites for collection of samples. Samples will be stored in NHS Biorepository and analyzed within the British Heart Foundation Laboratory at the University of Glasgow.