Hundested, Denmark

Evaluation of Oral Tofacitinib in Children Aged 2 to 17 Years Old Suffering From Moderate to Severe Ulcerative Colitis

Neoadjuvant Immune Checkpoint Inhibitor Treatment in Urothelial Cancer

Mechanisms of Excess Risk in Aortic Stenosis

Valvular heart disease (VHD) affects around 1.5 million people above the age of 65 across the UK and is set to nearly double by 2050. Aortic Stenosis (AS) is the most common VHD in the UK, affecting 3% of those over 75 with more than 11,000 people requiring aortic valve replacement (AVR) in the UK each year (>100,000 world-wide). Current guidelines recommend AVR to improve survival and symptom status when AS symptoms emerge or there is a reduction in left ventricle (LV) function (1), but years of excessive haemodynamic load result in an "AS cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar. The investigators, and others, have shown that these changes lead to an excess in morbidity and mortality, but the mechanisms of increased risk is unclear. Patients undergoing aortic valve replacement for severe aortic stenosis have a shorter life expectancy compared with the general population (2). Years of excessive haemodynamic load result in an "AS cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar. The investigators and others have shown that these changes to the heart muscle are associated with poor outcome. But the mechanism of how heart muscle damage leads to excess mortality is poorly understood. The proposed study will enhance our understanding of the residual risk after AVR and reveal the modes and substrate of mortality. Heart failure and heart rhythm disturbances (arrhythmias) are likely downstream effects of heart muscle damage, but without understanding the mode of death (heart failure, arrhythmia or other), the investigators are unable to target therapeutic strategies to improve outcomes.

Effect of Premedicant Oral Paracetamol on Gastric Volume and pH

Patients are asked to fast before anaesthesia to reduce the risk that residual gastric contents could be regurgitated and aspirated into the lungs once anaesthetised. In animal studies, gastric contents that are less acidic (with a pH >1.8) have been shown to be less harmful when aspirated than those that are more acidic, even at higher gastric residual volumes. Recent European and UK guidelines have reduced the length of the recommended clear fluid fast to 1 hour for children, as there is no significant difference in GRV or pH in children fasted for 1 hour compared to 2 hours. It is therefore believed to present no additional risk of harm. Some anaesthetists administer oral paracetamol syrup to children pre-operatively as an alternative to intravenous administration of paracetamol during their surgery. The oral route has been suggested to be pleasant for children, cheaper, more convenient, and reduce the risk of drug errors associated with the IV preparation. Anderson et al found no significant difference in gastric volume or pH in children with a mean age of 8.5 years given paracetamol orally 90 minutes before surgery compared to children given paracetamol rectally. Burke et al. demonstrated that giving paracetamol orally up to 8 minutes before induction of anaesthesia was not associated with an increase in the volume of stomach contents, and that the pH of stomach contents was higher than in control subjects who did not receive paracetamol. This suggests that giving oral paracetamol before induction of anaesthesia may not present any increased risk of harm from aspiration. This was in the context of a mean fluid fast of 5 hours and a mean age of 5.1 years. To our knowledge, no studies have assessed the effect of oral paracetamol syrup on gastric residual volume (GRV) and pH in the context of the newly recommended reduced clear fluid fasting time of 1 hour. Neither has this been studied in children as young as 44 weeks post-conceptual age.

FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma

FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS). It is a multi-arm, multi-stage format, involving several different trial questions. FaR-RMS is intended to be a rolling programme of research with new treatment arms being introduced dependant on emerging data and innovation. This study has multiple aims. It aims to evaluate the impact of new agent regimens in both newly diagnosed and relapsed RMS; whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent (in metastatic disease) and timing of radiotherapy improve outcome and quality of life. In addition the study will evaluate risk stratification through the use of PAX-FOXO1 fusion gene status instead of histological subtyping and explore the use of FDG PET-CT response assessment as a prognostic biomarker for outcome following induction chemotherapy. Newly diagnosed patients should, where possible, be entered into the FaR-RMS study at the time of first diagnosis prior to receiving any chemotherapy. However, patients can enter at the point of radiotherapy or maintenance, and those with relapsed disease can enter the study even if not previously entered at initial diagnosis. Patients may be entered into more than one randomisation/registration, dependant on patient risk group and disease status.

A 52-week, Placebo- and Active- Controlled (Roflumilast, Daliresp® 500µg) Study to Evaluate the Efficacy and Safety of Two Doses of CHF6001 DPI (Tanimilast) as add-on to Maintenance Triple Therapy in Subjects With COPD and Chronic Bronchitis. (PILLAR)

Outcomes of Digital Alerting Systems in Secondary Care

Psycho-educational Tool to Prevent Psychological Sequelae Following Paediatric Intensive Care Unit Admission

STUDY OBJECTIVES AND PURPOSE Aims - To systematically evaluate an innovative directed psycho-educational intervention consisting of written specific, age-appropriate information, complemented by a follow-up targeted telephone call in order to reduce psychological sequelae in the child and their parents/guardians after PICU discharge. - To confirm the effects of the psycho-educational tool on parent and child emotional adjustment 6 months after PICU discharge; and to explore whether these outcomes are associated with the child's age; with receipt of the targeted telephone call; and/or with parental levels of stress during the child's admission. - To obtain detailed feedback from parents/guardians and children about the different aspects of the psycho-educational intervention (the written information and the targeted telephone call) and the utility of these two psycho-educational interventions. Primary Objective To determine if the psycho-educational intervention is superior to treatment as usual in reducing parental post-traumatic stress and other psychological symptoms measured at 6 months after PICU discharge. Secondary Objectives - To determine if the intervention is superior to treatment as usual in reducing child post-traumatic stress and other psychological symptoms measured at 6 months post PICU discharge. - To determine whether the degree of parental stress during their child's PICU admission is particularly associated with the extent of psychological sequelae and whether the psycho-educational intervention is as less or more effective in the highly stressed families. - To determine if adding this relatively simple, innovative and pragmatic intervention to treatment as usual will provide a cost-effective use of NHS resources - To evaluate in detail child and parental acceptance of the intervention. Delivery of the Psycho-educational Tool and Assessment of Parental/Guardian Stress on PICU Discharge - Eligible families will include children 0-16 years admitted to PICU for > 24 hours, surviving to be discharged. - Parents who are deemed to lack adequate English Language to understand the written psycho-educational tool, telephone call and questionnaires will be excluded. [Our aim in future, if the intervention is shown to be successful, is to translate the intervention tools into the most frequently encountered foreign languages.] After obtaining informed consent prior to the child's discharge from PICU, a parental PICU stress screening questionnaire (18), will be given to all parents/guardians prior to discharge by the researcher or appropriately trained bedside PICU nurse. - Parents/guardians of all eligible children will be randomized using random allocation to receive either active intervention or treatment as usual (TAU). - Those randomised to the intervention group will be given the age-appropriate written psycho-educational tool prior to PICU discharge, by the researcher. The researcher will also explain the mechanism of the targeted telephone call to be delivered 4-6 weeks after PICU discharge. • Telephone Call: - All parents/guardians randomised to the intervention group will be offered the directed targeted telephone call from the researcher at 4-6 weeks post hospital discharge. - The researcher will use a protocolised, scripted interview questionnaire to discuss the contents of the tool and any psychological problems arising post PICU discharge, as well as provide information to families of ways of managing these, including, when appropriate referral to GP and local mental health services. - The study team will record the key outcomes of the call to include: Uptake rates and outcome; the number of families with impairing symptoms; and rates of referral to GPs and/or local mental health services.

Improving Ultrasound Based Prediction of Delivery Mode

Intrapartum Caesarean Delivery (ICD) in advanced labour has a greater fetal and maternal morbidity and mortality than an elective prelabour Caesarean delivery. The prediction of delivery mode may reduce the likelihood of intrapartum Caesarean delivery. There is also a parental desire to know the likelihood of vaginal delivery. Women admitted to delivery units throughout the world undergo internal digital vaginal examination (DVE) when they are thought to be in labour or where a diagnosis of labour needs to be discounted. DVE is an uncomfortable experience, multiple examinations have been linked to ascending maternal and fetal infection, and it is subjective method and not reliable technique to assess labour progress. It has recently become possible to make assessments more objectively using ultrasound. Ultrasound in labour (intrapartum ultrasound) has come to the forefront in the last decade stemming from a persistent demand for a more reliable method of labour assessment coupled with a wider availability of ultrasound on the delivery suite. The hypothesise in this study, that developing the previously derived proof of principle labour prediction model for nulliparous women and using an additional data could improve the prediction accuracy of intrapartum Caesarean delivery by developing a robust model. Using the additional data gathered in term nulliparous patients, will develop the model to predict pregnancy outcomes. This may aid in delivery of care to pregnant women by providing a real-time online calculation tool for the likelihood of Caesarean delivery and length of labour based on repeat ultrasound measurements. All participants will be identified by the researcher and an emphasis will be placed on recruiting patients antenatally as much as possible. All participating patients will be consented prior to enrolment and will receive a full explanatory information leaflet. If recruited antenatally, there is no time limit until the woman enters the delivery unit. If recruited in labour, then 2 hours will be considered appropriate to make a decision on whether they wish to take part and patient will only be approached when relatively pain-free (in between contractions). The admission ultrasound scan will include if feasible fetal Doppler assessment of the Umbilical Artery (Umb A) and Middle Cerebral Artery (MCA). Amniotic Fluid Index (AFI) will also be measured. The fetal position will be assessed with a transabdominal scan and recorded. Firstly, Umb A and MCA Doppler in addition to the fetal position and AFI, will be assessed with a transabdominal scan. After that, the transducer will be placed transperineally at the level of the posterior fourchette in a transverse position to measure HPD while caput succedaneum will be measured in a sagittal transperineal scan. The moulding will be assessed as either present or not. During the ultrasound examination, women will be in the supine position with flexed hips and knees and the bladder empty as previously described. Healthcare professionals will be blinded to the ultrasound findings, and these findings will also not be disclosed to the parents. Another doctor or midwife will perform all the ultrasound examinations. Subsequent scans will be performed as required at the time of routine clinical examinations typically between 2-4 hours apart but it may be longer. The healthcare professional will perform DVE for assessment of cervical dilatation in line with the National Institute of Health and Clinical Excellence (NICE) guidelines.

A Phase 1 Study to Assess the Immunogenicity of QL0605 Compared to US Neulasta in Healthy Subjects

This is a multi-center, randomized, double-blind, single-dose, 2-period parallel-arm study designed to assess the immunogenicity of QL0605 and US-Neulasta. A total of 300 healthy male and female subjects aged 18-55 years (inclusive) will be included and randomized to receive either 2 s.c. doses of QL0605 or US-NeulastaP®P in a ratio of 1:1. After the Screening Period of up to 4 weeks the subject will be randomly allocated to one of the 2 parallel treatment arms. All subjects will receive 1 s.c. injection of 6 mg QL0605 or 6 mg NeulastaP®P (US) in Treatment Period 1 and 1 s.c. injection of 6 mg QL0605 or 6 mg NeulastaP®P in Treatment Period 2. The interval between doses is ≥ 42 days.