Galle, Sri Lanka

Adult SMA Research and Clinical Hub

Spinal muscular atrophy (SMA) is a genetic motor neuron disease with a broad spectrum of severity, affecting both infants and adults. Advances in treatment, including Nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and Risdiplam (Evrysdi), have significantly improved patient outcomes, highlighting the need for stronger clinical networks to monitor the long-term effects of these therapies. The Adult SMA REACH Study builds upon the success of SMA REACH UK, which has been instrumental in collecting natural history and treatment data for paediatric SMA patients. The study benefits from collaboration with TREAT-NMD, the UK SMA Patient Registry, and iSMAC, aligning with international efforts to harmonise SMA data collection. By leveraging Newcastle University's experience in global SMA initiatives, Adult SMA REACH aims to enhance patient care, inform clinical decision-making, and contribute to future SMA research.

Multi-omics Study in Citrin Deficiency

Citrin deficiency (CD) is an inherited autosomal recessive metabolic condition that is also a secondary urea cycle disorder caused by mutations in the SLC25A13 gene, which encodes for the mitochondrial transporter, citrin. Citrin is a key component of the mitochondrial malate-aspartate shuttle (MAS) and is responsible for moving Nicotinamide Adenine Dinucleotide (NADH) from the cytosol into the mitochondria via reducing equivalents such as malate, which drives mitochondrial respiration to produce energy in the form of adenosine triphosphate (ATP). The MAS is also critical in regulating Nicotinamide Adenine Dinucleotide (NAD+/NADH) redox balance to maintain cytosolic redox-dependent metabolic pathways such as glycolysis, gluconeogenesis, amino acid metabolism, and lipid metabolism. Citrin is also required to supply cytosolic aspartate, which is the substrate of one of the urea cycle enzymes, namely argininosuccinate synthetase 1, and thus important for the proper functioning of the urea cycle. The clinical presentations of citrin deficiency often vary widely between patients but can generally be distinguished by distinct clinical phenotypes, which are neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) that affects infants, the "failure to thrive and dyslipidemia" form of CD (FTTDCD) in childhood, the adaptation or silent period, and citrullinemia type II (CTLN2), which represents the most severe form of the condition. While only a small percentage of CD patients develop CTLN2, the prognosis for these patients is typically poor. It is notable that all CD patients above 1 year old (post-NICCD) naturally develop a characteristic food preference that favors a diet rich in protein and fat while being low in carbohydrates. Other clinical findings observed in some CD patients include fatty liver, fatigue, hypoglycemia, and failure to thrive. There is currently no effective cure for CD. Before the onset of CTLN2, patients are primarily managed by diet control with a low carbohydrate, high protein and high-fat diet, as well as medium chain triglyceride (MCT) supplementation. CTLN2 patients have been treated with sodium pyruvate, arginine, and MCT with limited success, with severe cases requiring liver transplantation as the only solution. There are currently no specific biomarkers that effectively track the disease progression, making it challenging to monitor how well patients are actually doing or to measure the effectiveness of therapies. Without proper management or timely medical interventions, patients may develop CTLN2. Given the urgent and unmet need for biomarkers specific to CD, the main goal of this study is to uncover disease-specific biomarkers by analyzing blood samples collected from CD patients using both targeted and untargeted metabolomics, proteomics, lipidomics, and transcriptomics. Targeted omics will involve the analysis of cellular pathways associated with the condition, such as the MAS pathway, glycolysis, protein metabolism, de novo lipogenesis, lipolysis, gluconeogenesis, NAD+ metabolism, ureagenesis, and the glutamine synthetase pathway. Identification of such biomarkers will allow a deeper understanding of the disease pathogenesis. Importantly, these biomarkers may enable better tracking of disease progression and may help to prevent the onset of CTLN2. Finally, these biomarkers will also greatly benefit the development of effective therapeutic options for CD in clinical trials by serving as measurable endpoints. Obtaining the necessary material from patients consists of a minimally invasive venous blood sampling taken during a regular outpatient visit and after the informed consent of the patients or caretakers.

Open Label Trial Studying the Safety and Effectiveness of ILUVIEN® (190μg) in Children and Adolescents, Who Have Recurrent Non-infectious Uveitis Affecting the Posterior Segment of the Eye.

A Study on the Immune Response, Safety and the Occurrence of Respiratory Syncytial Virus (RSV)-Associated Respiratory Tract Illness After Administration of RSV OA Vaccine in Adults 60 Years and Older

A Study of MOv18 IgE in Folate Receptor Alpha-expressing Platinum Resistant Ovarian Cancer

EPS101-10-02 is a two-part, Phase Ib, open-label, dose escalation and expansion trial in patients with platinum resistant ovarian cancer whose disease has progressed after no more than 4 lines of standard therapy. In total, the trial will enrol approximately 45 patients. All enrolled patients will have biopsy accessible, measurable disease with a confirmed FRα expression of 5% or higher. MOv18 IgE will be administered to approximately 30 patients in Part 1 and up to a further 15 in Part 2. Patients will receive treatment on Days 1, 8 and 15 of a 21-day cycle and may continue treatment until radiological disease progression or unacceptable toxicity despite optimal medical management or dose or schedule modification, or withdrawal of consent. The starting dose of MOv18 IgE is 3 mg. Patient screening will occur during the 28 days prior to the first administration of MOv18 IgE. All patients will undergo PK, PD and safety assessments, as well as disease response (tumour) assessments to determine the potential clinical benefit of MOv18 IgE. In all instances, patients will be followed up for overall survival (OS) for a maximum of 270 days after their last dose of trial treatment, or until withdrawal of consent, lost to follow-up, death, or the overall end of trial, whichever is earliest. In Part 1, MOv18 IgE will be administered at increasing dose levels in different patient cohorts of approximately 6 patients, until selection of the Part 2 dose. The dose of MOv18 IgE administered in Part 1 will be escalated following a Bayesian logistic regression model - Escalation with overdose control (BLRM-EWOC) trial design. After determination of the Part 2 dose, up to 15 additional patients will be enrolled and treated with MOv18 IgE at that dose to further assess anti-tumour activity of MOv18 IgE and obtain additional information on its safety, PK and PD.

Efficacy, Safety, and Tolerability of Once Daily Oral Administration of AZD5004 Versus Placebo for 26 Weeks in Adults With Type 2 Diabetes Mellitus.

This is a Phase IIb, randomised, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy, safety and tolerability of AZD5004 in adults with type 2 diabetes mellitus, compared to placebo and active comparator. The study is planned to be conducted in approximately 15 countries, approximately 90 sites will be involved.

A Phase III Renal Outcomes and Cardiovascular Mortality Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin in Participants With Chronic Kidney Disease and High Blood Pressure

The purpose of this study is to investigate the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin, compared with placebo and dapagliflozin, in reducing the risk of the composite of > 50% decline in eGFR, kidney failure, or CV death, in individuals with CKD and HTN. This study consists of a 4-week dapagliflozin Run-in Period for participants untreated with SGLT2i at screening, and a double-blinded period where participants will receive either baxdrostat/dapagliflozin or placebo/dapagliflozin. Site visits will take place at 2-, 4-, 8-, 16-, 34, and 52-weeks following randomisation. Thereafter visits will occur approximately every 4 months. The study closure procedures will be initiated when the predetermined number of primary endpoint events is predicted to have occurred ie, the PACD. All randomised participants including any participants who have prematurely discontinued study intervention will be scheduled for a SCV within a few weeks of the PACD. This period can be extended by the Sponsor. In case of premature discontinuation of blinded study intervention, participants will continue in the study and receive dapagliflozin 10 mg, unless the participant meets dapagliflozin specific discontinuation criteria. If study intervention is temporarily or permanently discontinued, the participant should remain in the study, and it is important that the scheduled study visits (including the PTDV for participants with permanent discontinuation of study intervention) and data collection continue according to the study protocol until the SCV.

Development and Validation of a New Paediatric Inflammatory Bowel Disease NUTrition Risk Score (PIBD-NUTS)

Microvascular Coronary Rehabilitation For Improving Treatment - Feasibility Study

The investigators hypothesise that an intensified and personalised healthcare delivered lifestyle intervention (MICROFIT) will improve anginal symptoms in patients with microvascular coronary dysfunction. As a first step to a multi-centre randomised controlled trial (RCT) to establish efficacy, this feasibility study will test the components and acceptability of the intervention, alongside preliminary data on change in anginal symptoms to guide the powering of the subsequent RCT. Participants: The investigators aim to recruit 40 participants (men and women) with confirmed coronary microvascular dysfunction identified via existing clinical pathways (following an invasive coronary angiography study resulting in a diagnosis of microvascular angina) at two study sites, the Royal United Hospitals Bath NHS Foundation Trust (RUH) and University Hospitals Bristol and Weston NHS Foundation Trust(UHBW). Invasive coronary angiography with a microvascular study is a gold standard assessment for microvascular dysfunction nationwide and thus would be transferrable to all sites in the proposed subsequent multicentre randomised controlled trial. A named cardiologist at each site who will be a member of the research team will undertake the screening. Potential participants will be approached on the day of their attendance for microvascular dysfunction testing following the procedure, once microvascular dysfunction has been confirmed (as per inclusion criteria), or during a routine follow up appointment as part of usual care relating to the diagnosis of coronary microvascular disease. Potential participants will be informed of the experimental protocol both verbally and in writing before providing informed consent. The study will be conducted in accordance with the Declaration of Helsinki. Participants will be block randomised 1:1 using a web-based platform (Sealed Envelope: https://www.sealedenvelope.com/). Participants will be randomised to either usual care (control arm) or MICROFIT with usual care, in permuted blocks of four and stratified for sex. The control arm contributes to a robust assessment of feasibility (e.g. consent and attrition rates) and a comparator for the preliminary data on anginal symptom burden change. TRIAL ARMS: Usual care (control arm): All patients will be reviewed clinically by the Cardiologist performing the initial assessment. The cardiologist will address cardiovascular risk factors and prescribe any therapies, for example aspirin or statin therapy, as indicated by NICE guidelines. The Cardiologist will have over-arching responsibility for patients involved in the study, however, each patient's General Practitioner will be provided with a study information sheet and encouraged to adjust medications as needed according to national guidelines (e.g. for diabetic or hypertension management if these improve whilst participating in the study). The Cardiologist will also provide routine, verbal one-off lifestyle advice in line with NICE guidance, recommending 150 minutes of moderate exercise per week, encouraging a healthy, balanced diet, weight loss, reducing alcohol consumption and smoking cessation where necessary. The participants in the usual care arm will undergo the same assessments at baseline and at 24 weeks as the MICROFIT + Usual care arm, following which they will be offered a taster session with the personal trainer as well as information booklet regarding dietary advice offered to the participants in the MICROFIT + Usual Care arm. MICROFIT + usual care (intervention arm): MICROFIT is a lifestyle intervention designed to enable and support successful behavioural change with a predominant focus on exercise and diet. There is a focus on 1-on-1 delivery, higher intensity exercise, and updated dietary advice that aligns with the latest evidence-base for both microvascular dysfunction and broader cardiovascular disease. The programme will be explicitly introduced to each participant by the Cardiologist to ensure that the programme is presented as a meaningful intervention that can improve health outcomes. From the patient perspective, the Cardiologist will be seen as leading a multidisciplinary team, including exercise trainers and nutritional advisors, who are collectively working to improve the patient's microvascular function, measured both in terms of symptoms as well as objectively through stress perfusion MRI. The Cardiologist will introduce the concepts involved in the nutritional advice to the participant in the introductory session, provide advice and oversight to both the nutritional and exercise trainers throughout, and conduct further clinical reviews at the end of each intervention phase. MICROFIT has three phases: (1) induction, (2) consolidation and (3) maintenance. Below the structure of different phases of MICROFIT trial delivery is summarised. The exercise and dietary components are further explained in the next section. Phase 1 - Induction (8 weeks) Exercise: Twice-weekly 1-hour exercise trainer supervised exercise sessions (described below), with once-weekly sessions of prescribed moderate-intensity "homework". Weekly body metrics (BP, HR, BMI) will enable goal-setting and feedback to encourage adherence. Diet: Baseline 1-hour educational session with a dietician, followed by two 30 minute follow up sessions. These will be delivered virtually or face to face. Phase 2 - Consolidation (10 weeks) Exercise: Reduced supervised session frequency to once-weekly, with two sessions of prescribed moderate-intensity homework/week. Body metrics 2-weekly. Diet: 2x 30-minute "touch-base" sessions every 5 weeks, providing ongoing behavioural support of self-monitoring and goals. Phase 3 - Maintenance (6 weeks) Exercise: Supervised sessions reduced to one every 3 weeks, with three times/week prescribed sessions of homework (now higher-intensity aerobic exercise). Body metrics assessed at penultimate visit. Diet: A 30-minute "touch-base" session responding to changes in behaviour, where necessary. Below each component of the MICROFIT intervention is explained. Exercise Component: (i)Supervised Sessions: Experienced exercise trainers will lead supervised 1:1 exercise sessions incorporating HIIT based on the Norwegian4x4 model for CAD patients. At the start of each supervised exercise session, participants will be asked about any change in symptoms or medications and have blood pressure and heart rate measured. Participants will be taught the Borg Rating of Perceived Exertion (RPE; 6-20). The acceptable maximal heart rate will be calculated upon patient's age baseline CPET results, adjusted as recommended for patients taking beta-blockers. The first session will consist of a graduated, lead-in of moderate intensity exercise prior to commencement of HIIT in subsequent sessions. Supervised sessions will use a cardiovascular exercise (e.g. static bike or treadmill) and HIIT sessions will comprise a 3-minute warm-up; four 4- minute high-intensity intervals at RPE 15 (hard), finishing at RPE 17-18 (very hard); 3 minutes of active recovery at RPE 11-13 (somewhat hard) between each interval; and conclude with 5-minute recovery as is advised for patients with cardiovascular disease. Trainers will help maintain target intensity and monitor participants throughout for concerning symptoms. To enable this and mitigate risk, all trainers will be required to complete a MICROFIT training course that will incorporate symptom supervision, basic life support and defibrillator training. All exercise facilities will have a defibrillator on site. In addition, given the benefits of resistance exercise, especially for blood pressure control, the sessions will conclude with twenty minutes of resistance training. The exercise trainer will feedback power data to participants as they work through the programme to highlight visible progress being achieved. (ii) Homework Sessions: To enhance the weekly workload achieved and support long-term behaviour change, participants will be prescribed "homework" exercise sessions. This will comprise moderate-intensity aerobic exercise for 45-minutes in induction and consolidation phases (e.g., brisk walking), and increase to higher-intensity exercise (e.g., hill walking or jogging) in the maintenance phase. A once weekly resistance exercise session using workouts learnt in the supervised session during phases 1 and 2 will be added in phase 3. Participants will be provided with written guidance on effort levels, how to monitor their symptoms, and a HR monitor (MyZone) to support self-directed exercise intensity, ensuring their intensity is at the appropriate level. These data will be reviewed at supervised exercise sessions by personal trainers to evaluate progress and provide support and kept for subsequent analysis. Dietary Component: Patients will complete pre-session combined photographic/written diet diaries (retained by the research team for dietary analysis). Recognising that there is no "one-size-fits-all" pattern, the nutritional advisor will work with the patient to identify residual barriers to dietary change and potential solutions. The photographic diet diary will help highlight incremental areas for improvement in a straightforward manner. Where indicated, the dietician will also continue to highlight the importance of smoking cessation during sessions. The principles and guiding framework for the dietary advice will be: - Adoption of the Mediterranean-style diet in everyday diet - Reduced carbohydrate intake, focusing on avoidance of starch-based vegetables and refined grains - Reduced added sugars, using diet diaries to highlight "hidden sugars" - Drinking water (no smoothies, diet drinks, juices), unsweetened tea/coffee and alcohol in moderation - Avoidance of ultra-processed foods, e.g., highly-processed meat - Avoidance of "low-fat" products, in favour of natural, whole foods with unsaturated and/or mono-saturated fats - Increased dietary fibre - Focus on dietary patterns, including advice to eat at regular mealtimes and portion control rather than "calorie counting", alongside snack reduction and identifying healthy alternatives. The participants will be offered an information booklet regarding dietary advice which they will be able to refer to throughout the course of the study. TRIAL ASSESSMENTS: The trial comprises of five assessment episodes: 1. baseline assessment prior to participant randomisation, part of which is undertaken for convenience at the sametime as screening and consent visit 2. in-study assessment at 8 weeks 3. in-study assessment at 18 weeks 4. end of study assessment at 24 weeks 5. follow up qualitative interview 1 month after participant trial completion. Participants in the intervention arm will undertake assessments 1-5, whereas participants in the usual care arm will attend assessments 1 and 4 only. Assessments 1 and 4 will require attendance at RUH or UHBW (depending on participant's recruiting hospital), University of Bath and St Joseph's Hospital, Newport. Assessments 2 and 3 will require attendance at RUH or UHBW only. Assessment 5 will be undertaken face to face or virtually according to participant preference. In order to minimise travel and appointment burden for patients, part of baseline assessment 1 will take place at the same time as screening visit. During this visit some of the baseline clinical investigations will be undertaken (including blood tests (HbA1c, lipid profile, inflammatory markers),ECG, echocardiography (if not performed within last 6 months), body anthropometrics (height, weight, waist and hip circumference), clinic BP measurement and patient questionnaires (Seattle Angina Questionnaire, Hospital Anxiety and Depression Scale and EuroQol-5D-5L questionnaire for quality of life). The patients will also be issued blood pressure monitor for 7-day home BP monitoring and wearable activity device (GeneACTIV), alongside instructions for diet diary to be undertaken at home. The participant will also be made an appointment to attend Cardiac MRI at St Joseph's Hospital and CPET (cardiopulmonary exercise test to assess fitness levels) and body composition testing (DEXA) at University of Bath. This concludes baseline Assessment 1. Assessment 4, concluding the trial, will follow the same structure. Assessments 2 and 3 will take place solely with participants in the intervention arm of the trial. These visits will take place at RUH or UHBW and will comprise clinical review, blood tests, body anthropometrics and clinic BP. Assessment 5 will take place face to face or virtually and will comprise of a qualitative interview on participant experience in the trial. All 20 intervention participants will be invited for a 30 - 40-minute interview upon completion to capture all ranges of experiences of participation in the trial. Interviews will seek feedback on trial participation, including barriers and facilitators to trial procedures, exercise adherence, and explore any unanticipated effects of taking part. Encrypted interviews will be recorded, transcribed verbatim and analysed using both narrative and thematic analysis. In-depth (30 - 40 minute) interviews will be conducted with all practitioners involved in delivering MICROFIT to identify areas that need to be adapted or changed to implement the intervention in a future trial (or rollout). Specifically, this will include their experience of delivering and supporting MICROFIT, the quality of the training resources, and how participation affected their other work and relationships with patients. MICROFIT adherence measurement: Adherence to MICROFIT will comprise of attendance at supervised exercise and nutritional sessions, and participation in home unsupervised sessions. A summary of the assessments at each time points is shown in Trial Flowchart within trial Protocol.

Long-Term, Open-label Study of Oral Deucrictibant Extended-Release Tablet for Prophylaxis Against Angioedema Attacks in Adolescents and Adults With HAE

The study consists of a Screening Period during which eligibility is confirmed (only for participants not rolling over within 28 days from a previous deucrictibant prophylactic study), a Treatment Period in which participants will receive open-label deucrictibant extended-release tablet once daily for approximately 130 weeks, followed by an End of Study visit after maximum 4 weeks. Participants will undergo regular safety (e.g. lab draws) and efficacy assessments, will complete an electronic diary daily, and also complete questionnaires at predefined timepoints during the study.