Columbus, North Carolina

A Trial of 5 Fraction Prostate SBRT Versus 5 Fraction Prostate and Pelvic Nodal SBRT

This study will look at the safety of curative radiotherapy to the prostate and lymph glands given in 5 visits, in men with high risk localised prostate cancer. The purpose of the research is to test an advanced type of external beam radiotherapy called stereotactic body radiotherapy (also known as SBRT) in 1128 participants with high risk localised prostate cancer (that is, prostate cancer that has not spread beyond the prostate gland but is at high risk of growing quickly or spreading). Importantly, this treatment delivers a potentially curative dose of radiotherapy in only 5 treatments over two weeks. Half the participants in the trial will receive radiotherapy to the prostate, the other half will have radiotherapy to the prostate as well as the surrounding lymph nodes. The investigators will follow patients in the trial for at least three and half years to see which treatment is best. The investigators will be looking at whether it is safe to give this treatment by reviewing any side-effects that occur and also assessing whether giving SBRT to the lymph nodes as well as the prostate reduces the chance of prostate cancer returning. The treatment will take place at NHS radiotherapy centres that are experienced in giving SBRT and radiotherapy to the pelvic nodes, and have been quality assured to deliver these treatments

PROphylaxis for paTiEnts at Risk of COVID-19 infecTion -V

Part 1: Inhaled repurposed agents The trial commenced with the first intervention, nasal niclosamide and matched placebo from February 2021. The intended second intervention is nasal and inhaled ciclesonide. Participants are being randomised in a 1:1 ratio until the second intervention is introduced. Once ciclesonide is introduced, participants who are eligible for ciclesonide will be randomised to niclosamide, ciclesonide, niclosamide matching placebo or ciclesonide matching placebo in a 2:2:1:1 ratio. The net result will be a 1:1:1 distribution between niclosamide, ciclesonide and placebo, with niclosamide-matching placebo and ciclesonide-matching placebo pooled for the analysis. Three vulnerable patient populations were enrolled initially: dialysis patients, kidney transplant recipients and those with vasculitis or other auto-immune kidney disease such as systemic lupus erythematosus (SLE) or glomerulonephritis (GN) These patient groups are noted to be particularly vulnerable to COVID-19 infection by virtue of demographics, underlying co-morbidities or as a consequence of treatments for these conditions, and they are at exceptionally high risk of adverse outcomes. Additionally these groups are known to mount sub-optimal responses to vaccination. Approximately 1500 participants will be randomised to active treatment or placebo, stratified by PROTECT sub-population, age and participating sites. Enrolment to the trial will be via an online platform following informed consent with a face to face screening visit. The screening visit will include assessment of eligibility (which will include liver function tests and COVID-19 PCR test), randomisation, baseline data collection and research serum sample collection to detect anti SARS-COV-2 antibodies. Subsequent assessments, aside from an in person end of trial visit, will be done via email or telephone together with utilising the routine collected health data thus reducing the burden to participants as well as reducing their exposure to COVID-19. Telephone consultations will be carried out at weeks 1, 2, 3, 4 and 6, followed by two weekly self-reporting at week 8 onwards. If a participant has not submitted data for a period of approximately 6 weeks, they will be contacted by the local study team for a telephone interview to minimise loss to follow up. Failure to follow up a participant for more than 6 consecutive weeks will halt their trial treatment dispensation until communication has been restored. Failure to follow up a participant for more than 12 consecutive weeks will be considered loss of follow up and conclude their participation in the trial. If a participant develops symptoms suggestive of COVID-19 infection they should arrange an urgent COVID-19 test. They should notify their trial physician. Participants should continue taking trial medication (if self-administering medication) until advised to stop by a member of the trial team or admitted to hospital. Any participant testing positive for SARS-CoV-2 will be required to complete a COVID-19 symptom assessment at least weekly for 4 weeks after diagnosis, unless hospitalised. A final safety assessment will be conducted in person, 4-6 weeks after the final treatment. Participants will be asked to return all completed medication diaries and IMP containers, if self-administering, for compliance assessment at this visit. Participants will be asked a series of questions to identify any additional adverse events or adverse reactions experienced since their last follow up assessment and a blood sample will be taken for a SARS-CoV2 total antibody assay, to detect asymptomatic cases of COVID-19 infection. At the final assessment, patients may be re-screened for consideration of enrolment into one of the other arms of the PROTECT-V trial platform. It is not permitted for re-enrolment into the originally assigned arm. Participants will continue allocated treatment until one of the following occurs: 1. The required number of the primary outcome events have occurred (for each intervention) 2. The participant is hospitalised with COVID-19 (see 4.10.2.) 3. 28 Days after a diagnosis of COVID-19 if hospitalisation is not required The anticipated median treatment duration per participant is 6 months. However, the individual arm may conclude while some participants are in the trial for less than 6 months if the required number of events are observed. All Adverse Events and Adverse Reactions will be recorded in the medical notes and in the appropriate section of the case report form. Serious adverse events and serious adverse reactions should be reported to the sponsor. Niclosamide is a derivative of salicylic acid and has been used to treat tapeworm infections. The exact target and mechanism of action is uncertain. Researchers at Institut Pasteur Korea have reported niclosamide as one of the most potent FDA approved inhibitors of SARS-Cov-2 in in vitro assays using vero cells, with IC50 of 0.28μM >25x higher than that of chloroquine and >40x higher than that of remdesivir. In-vitro data indicating potent inhibition of SARS-COV2 replication and cellular penetration, together with evidence that SARS-COV2 initially replicates predominantly in the nasal epithelium, suggests nasal niclosamide is best placed as a prophylactic agent or for treatment of early stage COVID-19 disease when the viral load is a main issue. Hepatic clearance is the primary mechanism for elimination and there is anticipated low bioavailability, therefore no dose adjustments are required for patients with renal impairment. Side-effects (based on a phase 1 study in healthy volunteers) are minor nasal irritation, sneezing or runny nose. Population Pharmacokinetic (PK) assessment will be conducted in the first 30 participants receiving niclosamide for safety purposes, to exclude the unlikely possibility of accumulation of niclosamide during the course of the trial in patients receiving dialysis only. Ciclesonide is an inhaled corticosteroid (ICS) that has been shown to possess in vitro anti-SARS-CoV-2 activity. Ciclesonide inhibits in vitro SARS-CoV-2 replication in cultured human bronchial epithelial cells via a novel mechanism on non-structural protein 15 (NSP-15). ICS, particularly at higher doses, have been shown to reduce expression of ACE2 and TMPRSS2 receptors, which mediate infection of host respiratory epithelial cells. ICS have also been shown to inhibit in vivo production of IL-6, a key pro-inflammatory cytokine in COVID-19 and a major predictor of severe disease and poor outcomes. The proposed combination of prophylactic inhaled and intranasal ciclesonide will deliver early infection modifying therapy covering the entire respiratory epithelium, critical in the early stages of COVID-19. Ciclesonide and its active metabolite are metabolised and excreted by hepatic mechanisms, therefore no dose adjustments are required for patients with renal impairment, Side-effects may include cough, bronchospasm, bad taste and application site reactions. Part 2: Monoclonal antibodies and anti-viral agents Sotrovimab is a fully human IgG1κ monoclonal antibody (mAb) derived from the parental mAb S309, a potent neutralising mAb directed against the spike protein of SARS-CoV-2. S309 binds to a highly conserved epitope of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domain (RBD) and inhibits SARS-CoV-2 infection in vitro. Sotrovimab demonstrates high affinity binding to the SARS-CoV-2 spike RBD. COMET-ICE is a Phase II/III randomised, double-blind, placebo-controlled study which evaluated sotrovimab as treatment for COVID-19 infection in non-hospitalised patients at high risk of medical complications of the disease. The primary endpoint, progression of COVID-19 at Day 29, was reduced by 85% compared with placebo. A single dose of 500 mg was selected for the study based on in vitro neutralisation data, in vitro resistance data, and IV PK data from the COMET-ICE [NCT04545060] study. No dose modification is required in renal or hepatic disease. The overall rate of AEs in COMET-ICE was similar in those treated with sotrovimab compared to placebo. The known side-effects of sotrovimab are hypersensitivity and anaphylaxis. There will be a single infusion of sotrovimab or placebo administered at the beginning of the study. Based on the pharmacokinetics of the drug, it is predicted that the single infusion will remain efficacious for approximately 16 weeks. An absent or suboptimal response (Roche Elecsys® Anti-SARS-CoV-2 assay result <400 AU/mL) to COVID-19 vaccination, assessed at least 14 days after the vaccine was initially require to be eligible for the sotrovimab arm of the study however, this have been remove from the criteria. Additional patient groups with primary immunodeficiency, any Haematology or Oncology patient who is currently receiving or has received chemotherapy or who is immunocompromised as a result of their disease or treatment, those with a diagnosis of an autoimmune or inflammatory disease receiving immunosuppression and also haematopoietic stem cell transplant recipients have been added. In addition to the core components of the screening visit previously listed the following will also be conducted: ECG, serum antibody sample for Roche Elecsys® Anti-SARS-CoV-2 assay, full blood count, clotting profile, renal and liver function test (routine ALT/AST tests performed up to 2 week before screening visit will be accepted to assess liver function), and serum pregnancy test in women of child bearing potential, urine albumin: creatinine ratio. At the day 1 infusion visit, prior to commencing the IMP infusion, a blood sample to measure anti-drug antibodies will be collected. Routine observations must be taken prior to infusion, at the end of infusion and 1 hour after infusion and to be recorded. PK samples to be taken within 1 hour after end of infusion. Telephone consultations/remote telephone assessments will be carried out weekly for the first 4 weeks, alternative weeks from week 6 to 24 and then every 4th week from week 28 to 36. In person assessments will occur during weeks 4, 12 and 24 and will include blood sample collection for measurement of COVID-19 antibodies and PK sampling.

Clinical and Immunogenetic Characterization of Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR)

Giant cell arteritis (GCA), also known as temporal arteritis, is the most common form of primary systemic vasculitis, with up to 75,000 cases a year identified in the EU and US. It occurs almost exclusively in people over the age of 50 years and is considered to be a medical emergency. If not treated with high-dose glucocorticoids immediately, the thickening of the inflamed blood vessel wall can cause irreversible visual loss or stroke. GCA can lead to significant morbidity across a variety of systems, due to both the disease, and complications of treatment. Diagnosis may be confirmed with a temporal artery biopsy, imaging (e.g. USS/CT/MRA/PET-CR) or based on clinical signs (e.g. erythrocyte sedimentation rate) and symptoms (e.g. a new headache, jaw claudication, visual disturbances, temporal artery abnormality such as tenderness or decreased pulsation) . Polymyalgia rheumatica (PMR) is characterised by inflammatory limb-girdle pain with early morning stiffness, and a systemic inflammatory response demonstrated by elevated inflammatory markers. The UK GCA Consortium is a multi-centre observational study, the main arms of which recruit prospective (participants with suspected GCA) and retrospective cohorts (participants with confirmed GCA diagnosis). Analysis of data collected on these cohorts will help achieve the primary aim of finding genetic determinants of GCA and PMR susceptibility, in order to yield novel insights into disease pathogenesis. Secondary aims, and their associated analyses, are as follows: - Phenotype: characterising GCA and PMR subtypes, based on clinical features; imaging; cells; subcellular fractions and molecules in the circulation and/or arterial tissue; genetic/epigenetic/transcriptomic/proteomic or metabolomics factors, including next generation sequencing (whole exome sequencing) of selected cases. - Life impact: determining what aspects of the disease and treatments affect patients' quality of life, as assessed by patient-reported outcomes. - Long-term outcomes: characterising prognosis of GCA and PMR - both effects of the disease and its treatment - by longitudinal follow-up through electronic linkage to health records. - Exploratory analyses: exploring the potential role of environmental factors and co-morbidities on phenotype and outcomes. - Diagnosis, prognosis: improving diagnosis of GCA and PMR, and identifying factors that predict diagnosis, such as diagnostic clinical features, and prognostic and diagnostic biomarkers. - Disease activity: monitoring participants who commence a synthetic or biological disease-modifying anti-rheumatic drug (s/bDMARD). Finding a biomarker for GCA and PMR disease activity, which might be clinically useful in helping to optimise steroid and s/bDMARD treatments for individual patients.

VEST: The UK Vedolizumab Real Life Experience Study in Inflammatory Bowel Disease

Platinum and Polyadenosine 5'Diphosphoribose Polymerisation Inhibitor for Neoadjuvant Treatment of Triple Negative Breast Cancer and/or Germline BRCA Positive Breast Cancer

Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA. Disease under investigation: Breast Cancer Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy. Trial Design: Open label, randomised, 3-stage Phase II/III Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm). Non Investigational Medicinal Products: Prophylactic granulocyte-colony stimulating factor (G-CSF) to be given as per local practice and 3 cycles of anthracyclines as per local practice. Treatment period: A minimum of 21 weeks of chemotherapy followed by surgery. Procedures: Screening & enrolment Eligible patients with early breast cancer will be registered and consented for screening: BRCA mutation test Tumour Infiltrating Lymphocytes(TILs) score Cytokeratin 5/6 (CK5/6), Epidermal Growth Factor Receptor (EGFR) +/-, Androgen Receptor (AR) status by Immunohistochemistry (IHC). Standard assessment prior to chemotherapy Standard staging to exclude metastatic disease. When eligibility is confirmed, patients will be randomised via a web-based central system which will allocate each patient a unique randomisation number associated with one of the treatment arms. PARTNERing Pathway - For those patients who still have residual disease after receiving neoadjuvant chemotherapy +/- olaparib there is the opportunity to be screened to a sub-study to receive a further two cycles of chemotherapy consisting of Duralumab and AZD6738. End of Trial: For patients, the end of trial is after the last follow-up visit or contact with the research team planned 10 years after surgery. Procedures for safety monitoring during trial: Pharmacovigilance will be performed by the PARTNER Trial Office. Also, the Trial Management Group and the Independent Data and Safety Monitoring Committee will regularly review the patient safety data. Criteria for discontinuation of trial treatment on safety grounds: Severe toxicity or inter-current illness, requiring cessation in the judgement of patient's clinician. Patient within 4 weeks has not recovered from toxicity to an extent that allows further treatment. Patient unable to comply with trial procedures. Disease progression while on trial treatment. Patient becomes pregnant.

Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial

Intracerebral haemorrhage (ICH) is the most serious and least treatable form of stroke, accounting for at least 10% of the 20 million new strokes that occur globally each year. Survivors of ICH are at high risk of recurrent ICH and other serious cardiovascular events. While there is strong evidence that this risk can be reduced by lowering the blood pressure (BP) of patients after ICH, many patients with ICH do not receive BP-lowering treatment long-term unless BP levels are particularly high, and many do not receive BP combination therapy. The aim of this study is to assess the safety and efficacy of a combination of fixed low-dose generic BP lowering agents, as a "Triple Pill" strategy on top of standard of care for the prevention of recurrent stroke in patients with a history of ICH and high normal or low grade hypertension. The study is a large-scale, international, double-blind, placebo-controlled, randomised controlled trial.

Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

For further information, please visit: https://mnd-smart.org/