Le Plessis-bouchard, France

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

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.

Transthoracic Ultrasound Evaluation of Thoracic Aortic Aneurysms

It is important to state that patients involved in this study will not have any changes made to their routine care as a result of this study. All patients recruited would have had a recent CT scan which will be used for the comparison and will not be exposed to any additional radiation as part of the study. The CT scan used will be from the last 3 years so no new diagnoses are expected as a result of the study. Patients There will be two different groups recruited for this study; Group 1- patients with known thoracic aortic aneurysm (TAA) and Group 2- patients with known abdominal aortic aneurysm (AAA) but no thoracic aortic aneurysm. The known TAA group will be obtained from those who are currently having CT surveillance for either a known TAA or TEVAR (Thoracic Endovascular Repair). The known AAA but no TAA will be obtained from patients who are either under for CT surveillance AAA or EVAR (Endovascular Aneurysm Repair). All patients recruited for this study will be under CT surveillance at Southampton General Hospital or Queen Alexandra hospital and would have had a CT scan within the last 3 years at University Hospital Southampton so no new findings would be expected to come from the study. In addition, the CT scan used will be part of their routine care and there will be no change to their routine care or surveillance as a result of this study. Both Males and Female participants will be recruited for the study and there will also be a minimum age of 18 as gender will not influence the results of the study. Participant Recruitment Any patients eligible for the study will be contacted to see if they are interested in taking part and given a participant information sheet. The participant information sheet (PIS) will entail the full details of the study and what it will involve for the patient. If a patient is interested in participating in the study, a telephone call appointment will be arranged between a member of the research team and the patient. This phone call will involve going through the PIS, answering any questions, and obtaining verbal informed consent. During this appointment, an ultrasound scan appointment will also be arranged. A referral for the scan will be placed by Ben Patterson using the hospitals e-quest system under the patients hospital number so that images can be stored and a report can be generated and recorded for the patients record. The referral will placed using the code UAOTD and when the referral is on the CRIS system, one of the researchers will insure that the patient is changed to a research scan to ensure that it does not interfere with routine care. At the ultrasound assessment, written informed consent will be obtained prior to the scan being carried out and there will also be another opportunity for patients to ask any questions. If patients' are unable to consent to the study themselves as they are deemed to have a lack of capacity, they will not be included within the research study and will continue with their routine care. Collection of demographic data Patients age and gender will be recorded for the study. No other demographic information will be recorded. Ultrasound scan protocol A single vascular sonographer (Hannah Davey) will complete all ultrasound scans for this study and will be blinded to the CT diagnosis, location, and extent of the aortic pathology in all patients. This will be achieved by a member of the research team arranging the patients' appointment and having a study participant code for the scan referral so that the different groups cannot be identified. The vascular sonographer will also not complete any of the consenting in order to ensure they are blinded to any patient identifiable information. The maximum diameter (inner wall to inner wall) of the different areas of the thoracic aorta will be measured; primarily focusing on the descending thoracic aorta from the isthmus to the level of the diaphragm will be obtained and recorded for the study. The sensitivity and specificity of detecting TAA will be test at measurements of both 35mm and 40mm All scans of the thoracic aorta will be performed using a Philips Epiq 5 or Epiq 7 machine with 2 MHz phased array transducer. The patient will lay supine on an ultrasound scan couch which can be tilted in order to optimise the patient position and views required for the scan. The measurements will be taken in B-mode but colour Doppler imaging may be used to identify the thoracic aorta if it is obscured by artefacts. The measurement will be taken inner wall to inner wall and several images will be taken to check reliability. Three different acoustic windows will be used to image the thoracic aorta: 1. Suprasternal window- To visualise aortic arch and the three major supra-aortic vessels 2. Parasternal long axis window- To visualise the mid descending thoracic aorta 3. Apical two chamber views- To visualise the distal end of the thoracic aorta and proximal segment of the abdominal aorta Ultrasound assessment will be considered satisfactory when at least two of the three regions of the descending thoracic aorta were visualised, partially satisfactory when a single view was obtained and inconclusive when none of the three windows could be obtained The ultrasound scan appointment is estimated to take approximately 30 mins for obtaining written informed consent and completing the scan. All images and measurements taken during the scan will be stored on PACS and a report for the scan will be written on CRIS. CT Scan protocol A consultant vascular surgeon (Mr B Patterson) at Southampton General Hospital will review the CT scans and measure the maximum diameter (inner wall to inner wall) of the thoracic aorta. He is highly experienced in imaging patients with thoracic aortic pathology so the measurements will be reliable and valid. All CT scan measurements will be carried out on the picture archiving systems (PACS) at Southampton General Hospital and will also be compared to the measurement reported on system. Similarly to the ultrasound protocol, the maximum diameter of the different areas of the thoracic aorta will be obtained and recorded for the study. The diameter used for the study will be measured inner wall to inner wall in order to allow for comparison and accuracy to the ultrasound scan. The CT scan used for the measurement will be taken from the most recent aorta scan on the CRIS and PACS systems at Southampton General Hospital or Queen Alexandra Hospital. Patients will not be having any additional scans as part of this study and measurements will only be used from scans as part of their routine care. This is in order to minimise the amount of radiation each patient is exposed too and to make sure that their routine care is not interrupted by them participating in this study. Images from both the ultrasound scan and CT scan will be stored on a Picture archiving and communication system (PACS). Measurements of the maximum diameter for the ultrasound scan will be completed at the time scan and will be done using the measurement software in the ultrasound machine. The CT scan measurements will be carried out on the PACS system and will be compared to the value reported in the original report to check the accuracy. Measurements from both the ultrasound and CT scan will be recorded on Microsoft Excel. For each group, mean and standard deviation will be calculated. The sensitivity and specificity of the ultrasound scan will be analysed using cut-off points of both 35mm and 40mm. This will be done using the CT scan measurement as a reference for comparing the accuracy of the ultrasound measurement. Statistical analysis will be carried out on Statistical Package for the Social Sciences (SPSS). In order to calculate the sensitivity and specificity of ultrasound, a Clopper-Pearson confidence interval will be carried out on Statistical Package for the Social Sciences (SPSS). The statistical analysis will be completed with a 95% confidence interval and will be calculated at both 35mm and 40mm cut-offs.

Staphylococcus Aureus Network Adaptive Platform Trial

Infection of the bloodstream with the bacterium Staphylococcus aureus (Staphylococcus aureus bacteraemia, SAB) is a serious infection that results in 15-30% of affected patients dying within three months of acquiring the infection. Treatment of this infection requires patients to be hospitalised, treated with prolonged antibiotics through an intravenous line, and carefully examined for the occurrence of complications associated with this condition. At present, there are many treatment options in current use, with no clear agreement as to which of these is best. The SNAP trial aims to identify which treatment options for SAB results in the fewest patients dying within the first 90 days after an infection. In contrast to a conventional clinical trial, the SNAP trial will examine multiple different treatment options at once. Patients will be randomly assigned to different concurrent treatment options currently considered acceptable in routine medical care, but as the trial progresses, more patients will be assigned to treatments that appear to have better outcomes than those with worse outcomes. The trial will adapt to accumulating trial evidence, on a regular basis, by removing treatment options found to be inferior, incorporating new treatment options, and ensuring that all patients in the trial receive the best treatments once they have been identified. Over time, we hope to determine the best combination of treatment options for patients with SAB. The SNAP Trial infrastructure will also support a number of sub-studies. A list of all active sub-studies can be found on the SNAP website: https://www.snaptrial.com.au/substudies.

Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)

Mucus hypersecretion is a clinical feature of BE. This mucus-retention aids bacterial infection that can lead to pulmonary exacerbations, which further develops the "viscous cycle" of mucus-retention, infection, inflammation and tissue damage. Mucoactive drugs target this cycle by potentially increasing the ability to expectorate sputum and/or decrease mucus hypersecretion. The current guidelines indicate that mucoactives in combination with airway clearance may be considered to enhance sputum expectoration in BE, but the evidence to support their use is limited. Furthermore, evidence for the effectiveness of hypertonic saline (HTS) and carbocisteine is insufficient to recommend them within the management of BE. However, EMBARC/BRONCH-UK data show that BE centres do prescribe mucoactives. This is important because adherence to therapies in BE in general is low, decreases as the number of prescribed medications increases, and is also related to poorer patient outcomes, including the number of pulmonary exacerbations and quality of life. Therefore, it is essential that only those drugs that are effective should be prescribed for patients with BE. There are cost considerations associated with mucoactives, and there is a risk of polypharmacy side effects. Unlike BE, relatively strong evidence exists to favour the use of both HTS and carbocisteine within other respiratory conditions. Therefore, this trial will answer important clinical questions about whether similar benefits can be demonstrated in BE by using a pragmatic design to explore the specific effects of mucoactive agents, and directly support, or refute, more targeted use of these drugs. Patients will be randomised to one of four treatment groups: (i) standard care and twice daily nebulised HTS (6%), (ii) standard care and carbocisteine, (iii) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (iv) standard care alone.

A Controlled Study to Assess Safety, Colonisation and Immunogenicity of Reconstituted Lyophilised Neisseria Lactamica

In this pilot research, the research team will develop and validate a modification of the methodology previously used in another UK-based human challenge experiments. The research to be conducted in this study will inform the study team whether intranasal inoculation of reconstituted lyophilised Nlac (hereafter, lyoNlac), can result in immunising colonisation of participants and the optimal dose to achieve this. Previous challenges have been conducted using frozen stocks of Nlac but this is relatively unsatisfactory because of instability of frozen stocks, and will not be practical in Mali. The facility to reconstitute dry powdered lyoNlac into water and inoculate as a nose drop will greatly simplify the experimental method. However, it is not known whether lyoNlac can be inoculated directly into volunteers and induce successful colonisation. In summary this is a pilot study of the safety, efficacy and immunogenicity of the intranasal inoculation of healthy human volunteers with lyoNlac. This study will determine the efficacy of lyoNlac as an agent for inducing nasopharyngeal colonisation with this organism, which is an important methodological development for ease of administration of Nlac in experimental human challenge studies. The study team will aim to determine the dose of inoculum required to induce colonisation in 80% of volunteers (the Standard Inoculum or SI). This SI will be used in future studies aiming to optimise duration of colonisation and immunogenicity induced by lyoNlac.

PRIMUS 001: A Study Looking at Two Different Chemotherapy Regimens in Patients With Metastatic Pancreatic Cancer

PRIMUS 001 is a multicentre, randomised, open label, two arm, phase II interventional trial with pre-clinical and translational work including in-depth molecular profiling and biomarker discovery/development. The primary objective is to look at the efficacy of FOLFOX-A compared to AG in all comers and in a biomarker positive group using progression free survival.

SCIB1 and iSCIB1+ in Melanoma Patients Receiving Nivolumab With Ipilimumab or SCIB1 With Pembrolizumab (The SCOPE Study)

This is an open label, single arm Phase 2 study to determine the response rate and safety and tolerability of SCIB1 or iSCIB1+ when added to nivolumab (Opdivo) with ipilimumab (Yervoy) or SCIB1 with pembrolizumab (Keytruda). Pembrolizumab or nivolumab with ipilimumab are standard treatments already approved for the treatment of advanced melanoma. The plan for this study is for SCIB1 or iSCIB1+ to be given up to 11 times for 85 weeks, in combination with nivolumab with ipilimumab or SCIB1 with pembrolizumab. The standard treatments will be given according to the current label. The SCIB1 or iSCIB1+ injection will be given using PharmaJet needle-free injection device systems in the upper arm or upper leg. Before treatment starts and after consent has been given, all patients will undergo screening tests (to be completed within 28 days of treatment initiation) to ensure the patient is eligible to take part. Over the 85-week treatment period, the patient will visit the hospital multiple times and have some telephone/video calls. The evaluations and procedures that will be carried out at each visit are all detailed in the study information sheets given to the patient before consent is taken.

DURvalumab in Combination With S-488210/S-488211 vAccine in Non-muscle Invasive Bladder CancEr

DURANCE is a registered, phase Ib/II study in patients with surgically debulked bacillus Calmette-Guerin (BCG) unresponsive (resistant or relapsing) or intolerant non-muscle invasive bladder cancer (NIMBC). Patients will receive up to 24 weeks of durvalumab (a PD-L1 immune checkpoint inhibitor) in combination with S-488210/S-488211 (a 5-peptide cancer vaccine). Durvalumab will be given as 1500 mg IV infusion every 4 weeks for up to 7 doses, in combination with S-488210/S-S488211 which will be administered as two subcutaneous injections of S-488210/Montanide and S-488211/Montanide starting the day after the first durvalumab dose, then weekly for 6 doses and every 2 weeks for a further 9 doses (up to a maximum of 16 doses). All patients must have a cystoscopy at the end of week 12 (from start of trial treatment) for disease evaluation and to assess suitability to continue trial treatment. Patients with complete response, as shown from the cystoscopy, may continue treatment for up to 24 weeks in the absence of progressive disease, unacceptable toxicity or withdrawal of consent; all other patient will be withdrawn from further trial treatment. The phase Ib part of the DURANCE study will look to assess the safety and tolerability of the treatment combination of durvalumab + S-488210/S-488211 by reviewing Dose Limiting Toxicities (DLTs) which have at least a reasonable possibility of being related to the trial treatments (durvalumab and/or S-488210/S-488211). Up to 14 evaluable patients will be registered into phase Ib and provided the DLTs do not exceed the DLT thresholds defined in the trial protocol, the trial will proceed to the expansion phase of the study (phase 2). In phase 2 the trial will look to assess the disease free survival rate at 1 year following start of treatment.

MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation. There will be no cross-over either between arm A and B or between therapies on Arm B HC and IFN will be provided as best available therapy, IFN can include standard of pegylated-interferon at Investigators discretion.