Gillingham

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.

Migraine is a disease that most often causes moderate to severe headache on one side of the head. A migraine attack is a headache that may be accompanied by throbbing, nausea, vomiting, sensitivity to light and sound, or other symptoms. The goals of the study are to evaluate adverse events and how well treatment of atogepant works compared to placebo (looks like the study treatment but contains no medicine) in preventing chronic migraine in participants between 12 and 17 years of age. Atogepant is a medicine currently approved in the United States and Europe for the preventive treatment of migraine in adult patients with migraine and is being studied for the preventative treatment of chronic migraine in participants between the ages of 12 and 17 years. Participants will be randomly assigned to one of the 2 groups to be treated with either atogepant or placebo. This study is double-blinded, which means that neither the patients nor the study doctors know who is given which study treatment. Approximately 420 participants 12 to 17 years of age with chronic migraine will be enrolled at approximately 70 sites across the world. Participants will receive oral tablets of atogepant or placebo once daily for 12 weeks and will be followed for 4 weeks. Participants will attend regular visits during the study at a hospital or clinic and the effects of treatment will be checked by completion of a daily diary, medical assessments, blood tests, checking for side effects, and completing questionnaires.

A migraine is a moderate to severe headache on one side of the head. A migraine attack is a headache that may be accompanied by throbbing, nausea, vomiting, sensitivity to light and sound, or other symptoms. A number of treatments are available for adults with migraine but there are limited approved treatments available for pediatric participants. The main goal of the study is to evaluate the safety and efficacy (how well treatment works) of a low-dose and high-dose of atogepant in pediatric participants between the ages of 6 and 17. Atogepant is a medicine currently approved to treat adults with migraine (0 to 14 migraine days per month) and is being studied in pediatric participants between the ages of 6 and 17 with a history of episodic migraine. This is a Phase 3, randomized, double-blind study of atogepant in participants with a history of episodic migraine with an open-label pharmacokinetic substudy. Eligible participants will be randomized into 6 different groups. Participants between the ages of 12 and 17 will be randomized to receive placebo, low-dose atogepant, or high-dose atogepant for 12 weeks. Participants between the ages of 6 and 11 will also be randomized to receive placebo, low-dose atogepant, or high-dose atogepant for 12 weeks. The specific atogepant doses to be used in participants between the ages of 6 and 11 will be determined after the PK substudy is complete. Around 450 participants will be enrolled in approximately 100 sites worldwide. Placebo, low-dose atogepant, and high-dose atogepant are given as a tablet to take by mouth once a day. At the end of Week 12, participants will either undergo a follow-up visit 4 weeks after last study treatment or join an extension study where they can continue to receive atogepant for another 52 weeks. There may be a bigger responsibility for participants in this study. Participants will attend regular visits during the study at a hospital or clinic. The effects of treatment will be checked by medical assessments, blood tests, checking for side effects, and completing questionnaires.

This is a multinational, multi-center, observational, prospective, longitudinal disease registry designed to collect data on participants with cold agglutinin disease (CAD) or cold agglutinin syndrome (CAS). Among them, a minimum of 30 patients with CAD treated with sutimlimab are expected to take part in the sutimlimab cohort study. Patients with CAD who have been enrolled in previous sutimlimab clinical trials (e.g., BIVV009-01/LTS16214 \[NCT02502903,CAD patients\], BIVV009-03/EFC16215 \[NCT03347396\], and BIVV009-04/EFC16216 \[NCT03347422\]) and who either completed or discontinued the corresponding clinical trial are eligible to participate in the registry.

COMET is a phase III prospective multi-centre open label two-arm randomised controlled trial with an internal pilot and masked outcome assessments. Administration of cooling therapy cannot be masked. All babies born at or after 36 weeks and requiring prolonged resuscitation at birth (defined as continued resuscitation at 10 minutes after birth or 10-minute Apgar score less than 6) or those with severe birth acidosis (defined as any occurrence of: pH =\<7.00 or Base deficit \>=16mmol/l in any cord or baby gas sample within 60 minutes of birth) and admitted to the neonatal unit will started on aEEG or EEG as a part of standard clinical care. Neonatal doctors or advanced nurse practitioners (clinical team) will screen for eligibility using a structured neurological examination performed between 1 to 6 hours after birth. Once parental consent is obtained, babies will be randomised to whole-body hypothermia or targeted normothermia within 6 hours of birth, using a web-based program. Initial assessment and randomisation (and initiation of whole-body hypothermia or targeted normothermia) will occur at the hospital of birth. The babies in both arms, who are born at a non-cooling centre (LNU or SCBU) will be then transferred to the nearest cooling centre (NICU) within 8 hours of birth for continued care. Whole-body hypothermia (33.5±0.5°C) will be initiated within 6 hours of birth and continued for 72 hours using a servo-controlled cooling machine at the nearest available neonatal intensive care unit (cooling centre). Passive cooling methods will not be allowed. Whole-body hypothermia to 33.5±0.5°C for 72 hours is the duration and depth of cooling that is standard for babies with moderate or severe HIE in high income countries. To administer this intervention babies will be kept on a cooling mattress or blanket circulating a coolant/water, a rectal temperature probe will be inserted, and overhead radiant warmers will be switched off. The cooling device will be set to hypothermia mode and body temperature will be rapidly reduced to 33.5°C from 37.0°C and maintained within the target range of 33°C to 34°C. In the Normothermia (Control group), the rectal temperature will be maintained at 37.0±0.5°C for the first 88 hours and any hyperthermia will be treated with a standardised protocol. Four hourly axillary temperature will be recorded during the first 88 hours. Babies in the control group who develop seizures (level 1 or level 2) and progress to moderate HIE between 6 to 24 hours may be treated with whole-body cooling for 72 hours as clinical care, although this is expected to occur in less than 5%. Conventional MRI using standard 3D T1-weighted and 2D T2-weighted sequences and diffusion weighted imaging will be performed prior to discharge home. The follow-up assessment will be done when the recruited babies are 24 (±2) months of age. The assessment will be carried out using the Bayley Scales of Infant and Toddler Development IV. It is a validated and standardized scoring system that assesses development in three domains, that is cognition, language, and motor development. In addition, all infants will have a detailed neurological examination, including Gross Motor Function Classification System (GMFCS) for cerebral palsy, vision, and hearing assessment. Babies who die (the mortality rate is expected to be less than 1% in mild HIE) or who cannot be assessed with the Bayley-IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score (i.e., score of 54). In all infants, PARCA-R (online or face to face) will be completed by the parents immediately prior to the Bayley IV assessments and CBCL (face to face only) after the Bayley IV assessments. The data will be collected into a paper case report form (CRF) initially and then entered into electronic database at the participating sites. Data will include ante-natal, birth, and neonatal clinical information including gestational age, birth weight, gender, Apgar scores, birth history, delivery room resuscitation to assess the baseline comparability of the groups, core body temperature for assessment of intervention, details of the hospital course, laboratory investigations and MR imaging for safety monitoring, and neurodevelopmental outcomes at 24 (±2) months of age for primary outcome evaluation.

This is a multi-centre, randomised, non-inferiority, phase III study in patients with low risk differentiated thyroid cancer. Patients will be identified via oncology multidisciplinary team meetings. There will be two sources of patients in the trial, with the same histological diagnoses and prognosis (i.e. recurrence risk): * Group 1: Patients who have already had a HT for thyroid problems and are then subsequently diagnosed with low risk DTC will be randomised 1:1 to undergo surveillance only OR a second operation to remove the rest of their thyroid gland (two-stage total thyroidectomy). * Group 2: Patients diagnosed with low risk DTC using cytology (Thy5) but no surgery performed will be randomised 1:1 to have either a hemi-thyroidectomy OR a single-stage total thyroidectomy. The overall aim of the trial is to determine whether hemithyroidectomy is an acceptable and cost-effective surgical procedure compared to total thyroidectomy in low risk thyroid cancer. Overall, 456 patients will be recruited to the trial. Patients will be initially be followed up post-surgery then 12 monthly for 6 years.

Background and study aims: The aim of this study is to improve the way prostate cancer is diagnosed by looking at two different types of MRI scans and two different types of prostate biopsy (tissue samples). A large study such as this is required to help the NHS decide how to diagnose prostate cancer in the future. If a person is suspected of having prostate cancer, then they are referred by their GP. At the hospital clinic, the participant will then have an MRI scan. If this scan shows that cancer might be present, then the doctor will usually suggest that the patient has a biopsy. There are two ways of doing a prostate MRI. One takes 30-40 minutes and requires a contrast injection called gadolinium (like a dye). This is called long MRI and is most commonly used in the NHS. Gadolinium is safe as it rarely causes any bad reaction but using it means that the scan takes more time. Another type of MRI takes 15-20 minutes and does not use gadolinium contrast. This is called a short MRI. Many studies over the last 5 years have shown that the long and short MRIs are similar in their accuracy in diagnosing important prostate cancer. These studies have not been of high quality or large enough to change NHS practice. Patients with suspicious areas on the MRI are usually advised to have a prostate biopsy. This involves taking tissue samples using a needle. The samples are then looked at under the microscope by a pathologist to see if cancer cells are present. There are two ways of doing a prostate biopsy. One is where the person doing the biopsy decides where to put the biopsy needle by looking at the MRI scans that have been already taken on a computer screen. The needle is guided to the prostate using live ultrasound scans that are shown on a different screen near the patient. The biopsy operator makes a judgement about where to place the biopsy needles. This is called visual registration. Tissue samples from other areas of the prostate that look normal on the MRI scans are also taken to ensure cancer is not missed. The other type of biopsy is called image fusion. During image fusion biopsy, the biopsy operator uses the MRI scans that have been taken beforehand but laid on top of the live ultrasound images during the biopsy. This uses software and takes a few minutes longer to perform. Once the MRI images and ultrasound images are 'fused', the actual biopsies are taken as normal. Studies over the last 5 years have shown mixed results. Some have shown that image fusion biopsy is no better than visual registration biopsy, whilst a few have shown it might make a difference in improving cancer detection. As a result, it is not known for certain which way is better. A large study is needed to show whether the investigators need to do image fusion or not, in order for the NHS to decide whether or not to use it in all hospitals doing prostate biopsies.

An automated strategy for identifying abnormalities in head scans could address the unmet clinical need for faster abnormality identification times, potentially allowing for early intervention to improve short- and long-term clinical outcomes. Radiologist shortages and increased demand for MRI scans lead to delays in reporting, particularly in the outpatient setting. Furthermore, there is a wide variation in the management of incidental findings (IFs) discovered in 'healthy volunteers.' The routine reporting of 'healthy volunteer' scans by a radiologist poses logistical and financial challenges. It would be valuable to devise automated strategies to reliably and accurately identify IFs, potentially reducing the number of scans requiring routine radiological review by up to 90%, thus increasing the feasibility of implementing a routine reporting strategy. Deep learning is a novel technique in computer science that automatically learns hierarchies of relevant features directly from the raw inputs (such as MRI or CT) using multi-layered neural networks. A deep learning algorithm will be trained on a large database of head MRI scans to recognize scans with abnormalities. This algorithm will be trained to classify a subset of these scans as normal or abnormal and then tested on an independent subset to determine its validity. If the tested neural network demonstrates high diagnostic accuracy, future research participants and patients may benefit, as not all institutions currently review their research scans for incidental findings and clinical scans may not be reported for weeks in some cases. In both research and clinical scenarios, an algorithm could rapidly identify abnormal pathology and prioritize scans for reporting. In summary, the aim is to develop a deep learning abnormality detection algorithm for use in both research and clinical settings.

Community-acquired pneumonia (CAP) that is of sufficient severity to require admission to an intensive care unit (ICU) is associated with substantial mortality. Patients with pneumonia who are being treated in an ICU will receive therapy that consists of many different treatments, as many as 20 or 30. These treatments act together to treat both the infection and its effects on the body. When treating a patient, doctors choose from many different treatments, most of which are known or believed to be safe and effective. However, doctors don't always know which treatment option is the better one, as individuals or groups of individuals may respond differently. This study aims to help doctors understand which treatments work best. This clinical study has been designed in a way that allows the information from patients already in the study to help new patients joining the study. Most studies aren't able to do that. REMAP-CAP has been designed to: * Evaluate multiple treatment strategies, at the same time, in the same patient. * Reach platform conclusions when sufficient data is accrued, rather than when a pre-specified sample size is reached * Utilise data that is already accrued to increase the likelihood that patients within the trial are randomised to treatments that are more likely to be beneficial * New questions can be substituted into the trial as initial questions are answered, meaning that the trial can be perpetual or open-ended * Interactions between interventions in different domains can be evaluated It is reasonable to presume that any pandemic respiratory infection of major significance to public health will manifest as life-threatening respiratory infection including Severe Acute Respiratory illness and severe Community Acquired Pneumonia (CAP) with concomitant admission to hospital, and for some patients, admission to an Intensive Care Unit (ICU). Previous pandemics and more localized outbreaks of respiratory emerging infections have resulted in severe CAP and ICU admission. Previous pandemics and outbreaks of emerging infectious diseases have outlined the urgent need for evidence, preferably from Randomized Controlled Trials (RCTs), to guide best treatment. However, there are substantial challenges associated with being able to organize such trials when the time of onset of a pandemic and its exact nature are unpredictable. As an adaptive platform trial that enrolls patients during the interpandemic period, REMAP-CAP is ideally positioned to adapt, in the event of a respiratory pandemic, to evaluate existing treatments as well as novel approaches.

Waldenström's macroglobulinaemia (WM) is a rare type of slow growing lymphoma. It develops when white blood cells grow abnormally. Typically a disease of the elderly, the median age of presentation is \>70 years and the current treatment for WM is unsatisfactory, with incomplete responses and inevitable recurrence. Therefore there is a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. The RAINBOW study is a phase 2-3 trial assessing 'chemotherapy free' treatment as primary therapy for WM which can potentially improve response outcome, durability and importantly, reduce toxicity for WM patients. This approach will be done using the drug Ibrutinib, which in combination with rituximab (RI) will be the experimental arm. As there is no agreed standard on first-line therapy for WM, the control arm is the current treatment based on the most recently published clinical trial results. The control arm consists of rituximab, cyclophosphamide and dexamethasone (DCR), and is widely recommended by international consensus as appropriate treatment for first-line therapy for WM. In this study, 148 adults (aged ≥ 18 years) with treatment naïve WM will be randomised on a 1:1 ratio to either the treatment or control arm. Randomised treatment lasts for a maximum of 6 cycles and response will be assessed following 3 cycles of treatment and completion of randomised treatment at approximately 24 weeks after commencing treatment. RI patients may then have up to 5 years of Ibrutinib monotherapy. Patients will be seen regularly during treatment and then every 3 months for 5 years after treatment discontinuation. Patients will enter annual follow up for survival until the end of trial (including progressed patients). The study will be conducted at NHS hospitals and is expected to last 9 years and 6 months.