Whiston, United Kingdom

Hemithoracic Irradiation With Proton Therapy in Malignant Pleural Mesothelioma

Study design: Randomised phase III clinical trial for patients with unilateral MPM. Primary endpoint: Progression free survival (PFS) and overall survival (OS), defined as the time from randomisation to the date of progression and death from any cause. Secondary Endpoints: Safety and Tolerability, Health related Quality of Life (QOL): EuroQoL EQ-5D-3L, Locoregional Control. Randomisation and stratification: 1:1 randomisation. Patients with be stratified for histology (epithelioid versus non-epithelioid), potential PBT centre (UCLH or The Christie) , laterality (left or right sided) and time since diagnosis (<1 year or > 1 year) Treatment: Experimental Arm: Patients in the experimental arm will receive PBT to the hemithorax to a dose of 50Gy in 25 fractions with a boost to 60Gy for the visible tumour (gross tumour volume-GTV). Treatment is given daily Monday-Friday over 5 weeks. Following completion of treatment in the experimental arm patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. Control Arm: The patients in the control arm would be under standard of care surveillance i.e. "watch and wait", with no treatment or other intervention. Patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. If the disease progresses, the patient will receive SOC treatment i.e. immunotherapy with nivolumab and ipilimumab, or chemotherapy at the clinician's discretion. Statistical analysis plan: The sample size is 148 patients (74 patients per arm). This is to detect a OS hazard ratio of 0.58, equivalent to an improvement in 2-year OS from 30% to 50%, with 85% power and 5% two-sided alpha. Recruitment to complete in 3 years across 20 UK centres with 2 years of additional follow-up and up to 5% dropout. Interim analyses for OS efficacy will be performed when 50, 75 and 110 patients have been randomised at around 1.5, 2.0 and 2.5 years respectively. Using a fixed-sequence approach, a difference for OS will only be tested if the co-primary endpoint of PFS is statistically significant (p<0.05); N=148 will provide >85% power to detect a PFS hazard ratio of 0.58 accounting for up to 10% dropout.

Automated Fully Closed-Loop Insulin Delivery in Type 1 Diabetes With Ultra-Rapid Lispro (ACOLYTE Study)

Study Design An open-label, single-centre, randomised, 2-period cross-over study, in adults (18 years and older) with type 1 diabetes on insulin pump treatment. It is expected that up to 26 adults with type 1 diabetes will be recruited, aiming for 19 completed participants. The study flow chart is outlined in Figure 2. Study Subjects Study Population This is a single centre study and recruitment will take place at the Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester University NHS Foundation Trust. Up to a total of 26 adults aged 18 years and older with type 1 diabetes on insulin pump therapy will be recruited aiming for 19 completed participants. Potential participants will be identified by their treating clinicians and invited to contact the research team. They will be sent the study information leaflets and an invitation to join the study by the research team. Randomisation Eligible subjects will be randomised by the clinical researcher up to 14 days prior to first in-patient stay using Sealed Envelope randomisation software to undertake closed-loop studies in one of two possible random sequences; ultrarapid-acting lispro followed by insulin lispro, or insulin lispro followed by ultrarapid-acting insulin lispro. Study Schedule Overview The study will be co-ordinated from the Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester. The study will consist of five Visits including two 9-hour stays at the MCRF, Manchester Royal Infirmary, Manchester. Visits 1 and 2 may be combined. Tables 1 and 2 summarise the study visits. Recruitment Visit and Baseline Assessment (Visit 1) Once the subjects have agreed to participate in the study, they will be invited for the recruitment visit, when the following activities will be performed by the research team: - Written informed consent - Checking inclusion and exclusion criteria - Medical (diabetes) history - Body weight and height measurement; calculation of BMI - Record of current insulin therapy - Serum pregnancy test (females of child-bearing potential) Baseline Blood Sampling During Visit 1 consented participants will undergo a baseline evaluation where blood samples for HbA1c and serum beta HCG (pregnancy test) in females of child-bearing potential will be collected. Less than 15 ml of whole blood will be taken from each participant. In the event the laboratory HbA1c returns below 48 mmol/mol or above 86 mmol/mol the participant will be withdrawn. Training Session on Continuous Glucose Monitoring (Visit 2) This session will cover key aspects of the study CGM and attention will be paid to the following areas. This visit could be combined with visit 1. - Insertion and initiation of sensor session - Sensor calibrations - Use of CGM data to optimise treatment Written easy to use guidelines for the operation of CGM device will be provided. This session will be conducted by a professional pump educator / study nurse and possibly a member of the study team. Competency on the use of CGM will be assessed and additional training will be provided if deemed necessary by the Competency Assessment Form. Visit 3 - Optimisation During Visit 3, after a 2 to 3 weeks' run-in period, glucose control will be optimised, if required, by the study team with special focus on insulin to carbohydrate ratios. Manchester Diabetes Centre is the largest insulin pump centre in UK. We expect most of the participants in the study to be already well optimised. However, we will ensure this further by reviewing insulin, glucose and carbohydrate data during the two-week run-in period. Particular attention will be on the insulin carbohydrate ratio to see whether it is over aggressive. If the insulin to carb ratio is over aggressive this could potentially reduce the difference between Lispro and Lyumjev during the study. Participants whose glucose levels drops (those who develop hypoglycaemia within 2 to 3 hours of meal bolus) carb ratio will be adjusted to avoid this drop. Participants will also be randomised at visit 3. Visit 4 will follow within 2 weeks of Visit 3. Participants will be advised to avoid strenuous exercise 24 hours prior to each in-patient stay to avoid any bias arising from changes in insulin sensitivity. Activities during 9-hour in-patient stay (Visits 4 and 5, Figure 3) There will be two in-patient study days, performed within 1-6 weeks of each other. On each Study Day, participants will arrive at the study centre at approximately 08.30 and will be discharged by 18.00 the same day. Participants will be advised to insert a new CGM sensor 48 hours before the planned admission. A new insulin infusion cannula will be inserted on admission to the clinical research facility. In addition, participant will be advised to change their usual insulin to the corresponding study visit insulin formulation, 24 hours prior to admission. (For example; if the participant is on insulin lispro, this will be changed to ultra rapid-acting lispro 24-hour prior to the admission for closed loop with ultrarapid-acting lispro and vice versa.) Participants will be requested to fast from 12 midnight prior to admission (carbohydrate-free liquids are allowed). Participants will be requested to check their glucose between 05:00 and 07:00. If the glucose level is, or anticipated to be, < 4 mmol/l during this period, additional carbohydrate can be taken to aim for arrival glucose between 4 and 10 mmols. Correction insulin doses may be given if arrival glucose is anticipated to be above range (>10 mmol/l). Study visits may be rescheduled if participants develop significant hypoglycaemia (<3.0 mmol) or significant hyperglycaemia (glucose >20 mmol/l and/or ketones >0.6 mmol/l) 6 hours prior to or on arrival. On arrival, participant's usual insulin pump will be changed to study insulin pump. Closed-loop with either ultrarapid-acting lispro or insulin lispro will commence between 09:00 and 17:00 hours. A 60g meal will be served at 11:00 with no meal bolus to mimic a missed meal bolus. The study will end at 17.00. Patients will be switched back to their usual insulin pump therapy at the end of the study. Standard operating procedures will be in place for treatment of hypo and hyperglycaemia. Figure 3 summarises activities during the 9 hour in-patient stay.

HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia. Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.

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

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

Gene Therapy with Modified Autologous Hematopoietic Stem Cells for Patients with Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPSII, Hunter Syndrome) is a rare paediatric X-linked lysosomal storage disease caused by a deficiency in iduronate-2-sulphatase (IDS), due to a mutation on the IDS gene. IDS is essential for the breakdown of the sugar glycosaminoglycans (GAGs), in particular, heparan sulphate (HS) and dermatan sulphate (DS). Without this enzyme, these sugars accumulate in cells causing damage. Currently, enzyme replacement therapy (ERT) is the only clinically approved treatment available for MPSII. However, ERT is a supportive therapy and is intended to alleviate symptoms and improve patient quality of life, rather than addressing the pathogenic mechanisms of the disease. To date, there is no effective disease-modifying treatment. This study aims to recruit 5 patients with MPS II who satisfy the inclusion and exclusion criteria and provide full consent, between 3 months and 22 months of age at screening. The investigational medicinal product (IMP) will be a cell-based gene therapy that uses genetically modified autologous CD34+ haematopoietic stem cells transduced with a lentiviral vector containing the human IDS gene tagged with ApoEII. Patients will be followed up for a minimum of 2 years after gene therapy. The therapy works by adding the gene therapy to cells taken from the child's body. The cells are then frozen and tested for safety before being given back to the child. To collect the cells, we will give the child some medicine to mobilize hematopoietic stem cells (HSC) from their bone marrow into the blood which can then be easily collected. A working copy of the IDS gene is then placed into these cells in the laboratory (ex vivo). The modified HSCs are then given back to the child via a blood infusion where they can travel to and live in the bone marrow. In the bone marrow compartment, these cells will produce new blood cells that can make the IDS enzyme and can carry it around the whole body, including to the brain. This means the excess sugar chains can be broken down which may help cells to function normally. We think this will reduce MPS II symptoms and may help to prevent damage to the brain. To make sure the therapy is safe patients will be closely followed for 2 years within this trial. Additional follow up for a minimum 15 years post therapy or as per current guidance will then be offered.

A Study of JNJ-79635322 in Participants With Relapsed or Refractory Multiple Myeloma or Previously Treated Amyloid Light-chain (AL) Amyloidosis

Interferon-gamma as Adjunctive Therapy in Chronic Pulmonary Aspergillosis: a Randomised Feasibility Study

ARISTOCRAT: Blinded Trial of Temozolomide +/- Cannabinoids

This is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to compare the cannabinoid Nabiximols (Sativex®) with placebo in patients with recurrent MGMT methylated glioblastoma treated with temozolomide (TMZ). The trial will randomise a target number of 234 patients on a 2:1 basis to receive either Nabiximols or Nabiximols-matched placebo, in combination with standard TMZ. Patients will be followed up at 4-weekly assessments for a minimum of 52 weeks from the start of trial treatment or until death, whichever is sooner. MRI scanning will be performed at screening, week 10, week 22, week 30, then 3-monthly after commencing trial treatment as per standard practice. The trial includes an initial feasibility study of 40 patients to confirm safety, compliance and achievability of planned target recruitment. There are no formal criteria for evaluation of feasibility but once 40 patients have been recruited, the independent Data Monitoring Committee will review the adverse event data, details on protocol treatment received, monthly recruitment rates and projected recruitment in order to make recommendations on trial continuation. The current phase II trial design will enable potential expansion of recruitment into a phase III trial, should the emerging phase II results warrant this development. The trial will be linked to the Tessa Jowell BRAIN MATRIX (TJBM) programme; utilising TJBM infrastructure, opening the same participating sites, and aligning the data collection and Quality of Life assessments already embedded in TJBM. This collaboration will allow data sharing within the platform thereby streamlining patient entry and provide additional oversight through TJBM. Patients recruited to TJBM who are potentially eligible for ARISTOCRAT may be identified and suggested to sites for consideration to the trial.

Implementing an Intervention Named Volitional Help Sheets to Reduce Smoking Behaviour Among Young Adults in Indonesia

The main outcome measure is smoking abstinence; secondary outcomes are nicotine dependence, and capabilities, opportunities and motivations. All participants will be smokers aged 20-45 years who will complete self-report measures of outcomes over three waves of data collection. Once baseline measures are collected, participants will be randomised at wave 1 to intervention versus control condition. Participants in the intervention group will complete the VHS for smoking cessation in addition to the baseline measures. At wave 2, one-month following wave 1, participants will again be randomised to intervention (complete the VHS) and control condition. There will thus be four conditions: control, early intervention, late intervention and repeated intervention. Outcomes will be assessed at wave 3, six-months after wave 2.