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Chimeric antigen receptor T-cell (CAR-T) therapy - patient information

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This factsheet explains what chimeric antigen receptor T-cell (CAR-T) therapy is and what it involves so you know what
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Clofarabine

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Chemotherapy Protocol ACUTE MYELOID LEUKAEMIA CLOFARABINE In-Patient Regimen Clofarabine not licensed in adu
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/AML/Clofarabine.pdf

COV001_PIS_v5.0_21_Apr_2020_localised

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Southampton NIHR Clinical Research Facility University Hospital Southampton NHS Foundation Trust C Level West Wing, Mailpoint 218 Southampton SO16 6
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ClofarabineCytarabine

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Chemotherapy Protocol ACUTE MYELOID LEUKAEMIA ALL CLOFARABINE-CYTARABINE In-Patient Regimen Clofarabine not lic
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Current funding calls

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Auto Generated Title Here you can find new grant funding calls from various funders. Links on the right will take you directly to other calls with
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UHS register of interests June 2025

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Employee Name Aarvold, Dr Alice Beatrice Rachel Aarvold, Dr Alice Beatrice Rachel Adam, Dr Robert Dhugald (Rob) Adam, Dr Robert Dhugald
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ACCORD-2 example sub-protocol

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CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) TITLE PAGE Master Protocol Title: ACCORD-2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients Sub-protocol Number: ACCORD-2-002 Sub-protocol for Candidate Agent: Bemcentinib Study Phase: 2 Sponsor Name: University Hospital Southampton NHS Foundation Trust Legal Registered Address: Southampton General Hospital Level E, Laboratory & Pathology Block, SCBR - MP138 Tremona Road Southampton SO16 6YD, UK Regulatory Agency Identifying Number(s): EudraCT: 2020-001736-95 IRAS Number: 282769 RHM Number: Date of Sub-protocol: 22 April 2020 Version: Protocol Amendment 01 Caution: In accordance with cardiac exclusion criteria, in particular Exclusion 13, drugs known to cause QT prolongation should be discontinued/replaced, with sufficient time (5 half-lives) for washout. Patients in these categories of potential risk should be discussed directly by telephone with BerGenBio: Prof Hani Gabra, BerGenBio Chief Medical Officer: +44 7810 576112 Dr Akil Jackson, BerGenBio Medical Director: +44 7810 575037 Final, 22 April 2020 1 CONFIDENTIAL Sponsor Signatory: ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) I have read this sub-protocol in its entirety and agree to conduct this part of the study accordingly: Professor Tom Wilkinson MA Cantab MBBS PhD FRCP Professor of Respiratory Medicine and Honorary NHS Consultant Physician 22/04/2020 Date Final, 22 April 2020 2 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) TABLE OF CONTENTS TABLE OF FIGURES.............................................................................................................4 PROTOCOL AMENDMENT HISTORY .............................................................................5 1.0 SUB-PROTOCOL SUMMARY .................................................................................6 1.1 Overview of Sub-protocol................................................................................6 1.2 Schedule of Activities .......................................................................................8 2.0 BACKGROUND/RATIONALE IN SUPPORT OF BEMCENTINIB FOR COVID-19 .........................................................................................................12 2.1 Preliminary Efficacy Data vs with SARS-CoV-2 In vitro..........................13 2.2 Dose Justification for Bemcentinib...............................................................14 2.3 Human Experience from Trials in Cancer Patients ...................................16 3.0 STUDY POPULATION ............................................................................................18 3.1 Eligibility Criteria ..........................................................................................18 4.0 STUDY ASSESSMENTS AND PROCEDURES ....................................................19 4.1 Efficacy Assessments .....................................................................................19 4.2 Safety Assessments.........................................................................................19 4.2.1 Adverse Events ..................................................................................20 4.2.2 Clinical Safety Laboratory Assessments ...........................................20 4.3 Pharmacokinetic Assessments ......................................................................20 4.4 Pharmacodynamic Assessments ...................................................................20 5.0 STUDY TREATMENT .............................................................................................21 5.1 Conclusions and Risk Benefit Statement .....................................................21 5.2 Bemcentinib Drug Administration ...............................................................21 5.3 Dose Modifications and Toxicity Management ...........................................22 5.4 Prohibited Concomitant Medications ..........................................................22 5.5 Study Drug Information................................................................................22 5.5.1 Study Medication...............................................................................22 5.5.2 Bemcentinib Storage, Dispensing, and Destruction ..........................23 6.0 REFERENCES...........................................................................................................24 7.0 APPENDICES ............................................................................................................26 Appendix 1 Abbreviations ...................................................................................26 Appendix 2 Prohibited Concomitant Medication Due to QT Prolongation Risk or CYP3A4 Interaction with Narrow Therapeutic Index ..........................................................................................27 Final, 22 April 2020 3 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Appendix 3 Signature of Investigator ................................................................28 Figure 1 Figure 2 Figure 3 TABLE OF FIGURES Bemcentinib Potently Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection of Vero E6 Cells .............................14 Complete Inhibition of AXL Kinase Activation (p-Axl) in Two Acute Myeloid Leukaemia Patients Treated at the Recommended Phase 2 Dose (200 mg Maintenance Daily Dosing) .....................................................15 Bemcentinib Plasma Pharmacokinetics in Acute Myeloid Leukaemia Patients .............................................................................................................16 Final, 22 April 2020 4 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) PROTOCOL AMENDMENT HISTORY Protocol amendment 01 (dated 22 April 2020) replaces the original sub-protocol for bemcentinib (dated 20 April 2020). The amendment incorporates the following main changes: • A change of Sponsor, from BerGenBio ASA to University Hospital Southampton NHS Foundation Trust, with a corresponding change to the named Sponsor signatory. • Addition of exclusion criterion for clinically significant hypokalaemia. • Clarification that for the exclusion criterion of inability to swallow capsules, administration via nasogastric tube is permitted. • Clarification that the physical examination at screening includes height and weight (this is part of the Master Protocol). • Addition of samples for cytokine analysis and PBMC phenotyping on the Schedule of Activities (this is part of the Master Protocol). • Removal of specific blood volumes from the Schedule of Activities. • Clarified that analysis of inflammatory cytokines is part of the Master Protocol. • Clarification regarding known adverse events for bemcentinib. Final, 22 April 2020 5 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 1.0 SUB-PROTOCOL SUMMARY 1.1 Overview of Sub-protocol Bemcentinib is a small molecule AXL kinase inhibitor developed by BerGenBio ASA (the candidate agent owner) which has demonstrated potent and selective inhibition of AXL in biochemical and cell-based kinase inhibition assays. AXL is a recognised therapeutic target for the treatment of cancer. AXL regulates cancer cell survival and immunosuppressive modulatory effects, particularly in driving immunosuppressive features of the innate immune compartment in the tumour microenvironment, including activation of the myeloid derived suppressor cells, the M2 macrophage state, and suppressor regulatory dendritic cells that inhibit activated T cell function. Further, AXL is an important negative regulator of type I interferon (IFN) responses that are important for anti-cancer treatments. Bemcentinib is currently being developed for the treatment of cancer, particularly in non-small cell lung carcinoma, acute myeloid leukaemia (AML), myelodysplastic syndrome, and other cancers. The AXL receptor mediates entry of enveloped viruses such as Zika and Ebola through “apoptotic mimicry”. Phosphatidylserine (PS) on the viral envelope is tethered to AXL by its bound ligand, growth arrest-specific 6 (GAS6), leading to viral internalisation. Viruses also activate AXL signal transduction that antagonises anti-viral type-I IFN responses. Preclinical data show that AXL-mediated internalization and IFN suppression may extend to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and that bemcentinib can inhibit coronavirus entry and replication. The hypothesis is therefore that bemcentinib is a potentially effective treatment for COVID-19 disease. Additionally the Sponsor’s understanding of the mechanism supports testing the hypothesis that bemcentinib may be an effective preventive/prophylactic therapy for COVID-19. This sub-protocol describes the approach for study conduct of the bemcentinib arm within the ACCORD-2 multicentre, Phase 2 adaptive randomisation platform study to assess the efficacy and safety of multiple candidate agents for the treatment of COVID-19 in hospitalised patients. Key differentiating features of this sub-protocol include the following: (a) Bemcentinib is an oral 100-mg capsule, recommended Phase 2 dose (RP2D) is 200 mg given once daily, following a loading dose (400 mg) given once daily for 3 days. Although the Master Protocol plans for 15 days of treatment, this sub-protocol can provide up to 21 days of bemcentinib treatment if required for patients. (b) A specific eligibility criterion has been added to exclude patients based on electrocardiogram (ECG) QT interval on screening above 450 msec (a lower exclusion limit than that stated in the Master Protocol, 500 msec), as well as significant cardiac comorbidity. Any concomitant medication with QT prolongation risk must be stopped at screening and direct discussion between the investigator and Sponsor Medical Monitors will allow support in risk management. Serial ECG measurements have been added in Final, 22 April 2020 6 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) order to pragmatically monitor any QT interval change with bemcentinib, coupled to a sparse pharmacokinetic (PK) sample schedule, in the hospitalised COVID-19 population. Within the clinical development programme to date, over 286 patients have been treated without any observed cardiac adverse events (AEs). (c) Translational and pharmacodynamic (PD) sampling is included in this protocol. Detailed procedures for the collection, processing, storage and shipment of the samples will be provided in the Study Laboratory Manual. (d) Selected secondary endpoints from the Master Protocol will be considered as key secondary endpoints for the purposes of this sub-protocol. Final, 22 April 2020 7 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 1.2 Schedule of Activities Screening Baseline Day (± Window) ELIGIBILITY Informed consent Demographics Relevant medical historyb Review SARS-CoV-2 diagnostic tests Inclusion and exclusion criteria STUDY INTERVENTION Randomisation Administration of bemcentinibc Treatment with SoC STUDY PROCEDURES Clinical frailty score Diagnostic imaging (X-ray and/or computed tomography) Physical examination (including presenting symptoms, height, weight) Targeted physical examination (focused on lung auscultation) Day -1 or Day 1 Day 1 X X X X X X Days 1-3 400 mg loading daily X X X X Daily Until Hospital Discharge X 200 mg maintenance X X Day 15a (±2 days) X Day 29a (±3 days) Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Final, 22 April 2020 8 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Screening Baseline Day (± Window) Vital signs, including oral temperature, pulse rate, blood pressure, respiratory rate, SpO2 Clinical assessmentse Targeted medication review (including use of vasopressors) Adverse event evaluation Disease-related co-infection evaluation (including microbiologic/infectious agent assessment/results; bacteria, viral, fungi) Survival status Blood gases and FiO2 at worst PO2f 12-lead ECGg SAFETY LABORATORY Haematology, chemistry, liver function tests, coagulationh Pregnancy test for females of childbearing potential RESEARCH LABORATORY Blood (SST) for exploratory inflammatory cytokine analysis Blood (sodium heparin tube) for PBMC phenotypingl Day -1 or Day 1 X X Xi Xi Day 1 Xd Xd Xd X X X X X Xd,j X X Daily Until Hospital Discharge X X X X X X X See schedule belowg Days 3, 5, 8, 11 (all ±1 day) if hospitalised Day 8 Day 8 Day 15a (±2 days) X X X X X X Xk X X Day 29a (±3 days) X X X X X Xk X X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) X X X X Final, 22 April 2020 9 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Screening Baseline Day (± Window) Day -1 or Day 1 Day 1 Daily Until Hospital Discharge Day 15a (±2 days) Day 29a (±3 days) Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Blood (EDTA) for SARS-CoV-2 PCR (qualitative and quantitative) X Days 3, 5, 8, 11 (all ±1 day) if hospitalised X X Oropharyngeal/nasal swab for SARS-CoV-2 PCR (qualitative and quantitative) X Days 3, 5, 8, 11 (all ±1 day) if hospitalised X X Saliva for SARS-CoV-2 PCR (qualitative and quantitative) X Days 3, 5, 8, 11 (all ±1 day) if hospitalised X X Blood (SST) for SARS-CoV-2 serology research (host response) X Day 8 X X X Blood (PAXGENE) for transcriptome analysis (host genome)m X Day 8 X Blood (EDTA) host genome (host DNA)m X Mid-turbinate nasal swab viral genomem X Blood samples for PD and translational studiesn X See schedule belown X X X PK samplingn X See schedule belown X ECG=electrocardiogram; EDTA=ethylenediaminetetraacetic acid; FiO2=fraction of inspired oxygen; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; PO2=partial pressure of oxygen; RT PCR=reverse transcription polymerase chain reaction; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2; SoC=standard of care; SpO2=oxygen saturation; SST=serum separator tube. a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, in-person visits are preferred, but recognising that quarantine and other factors may limit the patient’s ability to return to the clinic, these visits may be conducted by telephone or with a home visit by study staff. For visits conducted by telephone, it will not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will also be performed, where possible, for patients who discontinue the study prematurely. b Medical history includes estimated date and time of first symptoms and number of co-morbidities (eg, respiratory, cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). Final, 22 April 2020 10 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) c Although the Master Protocol plans for 15 days treatment, this sub protocol can provide up to 21 days bemcentinib treatment if required for patients. Bemcentinib should be taken once per day, in the morning, on an empty stomach with water. Patients should not consume anything other than water for at least 1 hour after taking study drug. d Baseline assessments should be performed prior to study drug administration. e Includes ordinal score, National Early Warning Score 2 (NEWS2), oxygen requirement, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen supply or of any form of ventilation etc. f If done as part of SoC, blood gases results to be fully recorded with date and time. g ECG to coincide with selected PK and PD sampling timepoints, ie, pre-loading dose (Day 1); then pre-maintenance dose and 6 hours postdose (Day 4). Subsequently predose on Days 8 and 15. h For parameters, see Master Protocol i Laboratory tests performed in the 48 hours prior to enrolment will be accepted for determination of eligibility. j Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. k Additional safety laboratory evaluations to be performed on Days 15 and 29 only if patient is still hospitalised. l Samples collected for immediate laboratory processing and frozen storage. m Samples collected dependent on capacity of study centre, need for reduced study burden on staff, and potentially limited access to patients. n Procedures for the collection, processing, storage and shipment of the PK and PD samples will be provided in the Study Laboratory Manual. Sample collection to coincide with the ECGs, ie, pre-loading dose (Day 1); then pre-maintenance dose and 6 hours postdose (Day 4). Subsequently predose on Days 8 and 15. Final, 22 April 2020 11 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 2.0 BACKGROUND/RATIONALE IN SUPPORT OF BEMCENTINIB FOR COVID-19 Nonclinical in vitro and in vivo data suggest that bemcentinib might be useful for the treatment of early SARS-CoV-2 infection for which no medical countermeasures are currently approved, and support testing the efficacy of bemcentinib treatment among hospitalised adults with COVID-19. The AXL receptor tyrosine kinase promotes the infection of a wide range of enveloped viruses including pox-, retro-, flavi-, arena-, filo-, and alpha-viruses (Shimojima 2006, Brindley 2011, Meertens 2012, Dowall 2016, Meertens 2017). AXL increases viral infection through two mechanisms: 1) enhanced viral entry through “apoptotic mimicry”; and 2) suppression of anti-viral type I IFN responses. The AXL receptor and related receptors (Tyro3 and MerTK, collectively TAM) are important for the clearance of apoptotic cells (efferocytosis) by macrophages (Lemke 2019). Enveloped viruses co-opt this mechanism to expand tropism and enhance viral entry. GAS6, the AXL ligand, binds PS exposed on the surface of the viral envelope, tethering the viral particle to the AXL receptor and promoting uptake by phagocytosis. This mechanism of viral entry, based on PS exposure, is common to most enveloped viruses and is termed viral “apoptotic mimicry” (Mercer 2008, Bhattacharyya 2013). Binding of the viral particle to GAS6-AXL potently activates signal transduction through its tyrosine kinase domain to suppress type I IFN signalling and facilitate viral replication (Bhattacharyya 2013, Meertens 2017). AXL expression is induced by inflammation and serves as an innate immune checkpoint. AXL signalling suppresses viral-induced IFN responses via suppressor of cytokine signalling (SOCS)1/3, leading to increased viral replication in infected cells and decreased anti-viral defences of neighbouring cells (Huang 2015, Chen 2018, Strange 2019). Consequently, Axl-null mice are resistant to Zika pathogenesis likely due to a combination of reduced virus entry and enhanced IFN responses (Hastings 2019), indicating a potential role for AXL inhibitors as therapeutics during viral infection. Therapeutic AXL receptor inhibition ameliorated pulmonary pathology resulting from primary viral infection in experimental models, indicating an important role for AXL within the lung (Shibata 2014). During primary respiratory syncytial virus (RSV) infection, AXL inhibition increased the number of IFNg–producing T cells and natural killer (NK) cells, suppressed RSV replication and whole lung levels of interleukin (IL)-4 and IL-13. Also, the lethal effect of intrapulmonary H1N1 infection inflammation was reduced by AXL inhibition. AXL inhibition in infected mice increased the number of IFN-b–producing macrophages and dendritic cells and suppressed neutrophil infiltration. Final, 22 April 2020 12 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Bemcentinib is a clinical-stage, oral, selective small molecule AXL kinase inhibitor with well documented anti-viral effects in several systems. Bemcentinib is reported to block dengue, Ebola and Zika virus infections in several cell types including epithelial, fibroblast, endothelial, neuronal and myeloid cell types in in vitro cell culture and organoid systems. Bemcentinib treatment is associated with increased IFN signalling and reduced viral replication (Dowall 2016, Meertens 2017, Strange 2019). During the 2013/2014 Ebola virus (EBOV) outbreak, bemcentinib was 1 of 60 compounds evaluated by Public Health England as an experimental therapy for EBOV, using its Biosafety Containment Level 4 facilities at Porton Down. Bemcentinib 200 mg/kg/day starting 6 hours post viral challenge protected 1/6 EBOV infected guinea pigs from weight loss and early mortality in an 18-day in vivo mortality study (Dowall 2016), compared with 1/6 untreated animals surviving to Day 18 but exhibiting weight loss during the observation period. The authors concluded that bemcentinib may have had some protective effect in this model. 2.1 Preliminary Efficacy Data vs with SARS-CoV-2 In vitro Professor Wendy Maury, University of Iowa, conducted a preliminary analysis of the anti-viral effects of bemcentinib on SARS-CoV-2 in a Vero E6 cell line. As shown in Figure 1, bemcentinib incubation starting 1 hour prior to virus inoculation potently inhibited SARS-CoV-2 infection of Vero E6 cells in a dose-dependent manner. Other studies using vesicular stomatitis virus pseudotyped with SARS-CoV spike protein and a mouse betacoronavirus (mouse hepatitis virus [MHV]) showed that bemcentinib may both inhibit uptake and activate the IFN-mediated antiviral gene, ISG15, to control viral infection. SARS-CoV-2 cell tropism is likely to include PS dependent viral uptake and may target critical immune cell populations (eg, macrophages, dendritic cells) that produce IFN and mobilize anti-viral immunity. Importantly, delayed IFN signalling is characteristic of pathogenic human betacoronaviruses and correlates with disease severity in animal models, suggesting that early intervention with IFN-activating treatment may provide therapeutic benefit (Channappanavar 2016). Thus, AXL targeting is expected to attenuate SARS-CoV-2 pathogenesis both by limiting viral uptake and promoting innate antiviral immunity. Final, 22 April 2020 13 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Figure 1 Bemcentinib Potently Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection of Vero E6 Cells Vero E6 cells (60,000) in a 48-well format were incubated (1 hour) with bemcentinib prior to addition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (MOI 0.0005). Cells were lysed at 24 hours and viral load was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR) for spike protein gene expression as normalized to the housekeeping gene Cyclophilin. W.Maury et al., unpublished results Importantly, recent data that differentiate SARS-CoV-2 from severe acute respiratory syndrome (SARS) have emerged that support the hypothesis that AXL may have a more dominant role in SARS-CoV-2 infection, and therefore that bemcentinib may have specifically a more important role to play in inhibiting this viral infection: • SARS-CoV-2 has similar replication kinetics to SARS-CoV, but demonstrates differential sensitivity to type I interferon treatment (One of 2 mechanisms of action of Bemcentinib through AXL inhibition) (Lokugamage 2020). • Structural analysis of the spike (S) protein of SARS-CoV-2 showed that its S protein has weaker binding to the angiotensin converting enzyme (ACE)2 receptor on human cells compared with strong affinity of human SARS coronavirus (Dong 2020) – supporting the large magnitude effect we have observed for inhibition of viral replication using clinically appropriate doses of bemcentinib in ACE2 receptor +ve cells. 2.2 Dose Justification for Bemcentinib Bemcentinib’s antiviral action stems from a cellular effect, inhibiting AXL kinase to prevent viral attachment and intracellular viral replication (through maximisation of the early type-I interferon rather than a direct antiviral action). From estimates of pooled data, the half maximal inhibitory concentration (IC50) at 24 hours for bemcentinib inhibition of viral load is approximately 140 nM and the approximate concentration required for 90% of maximum inhibition (IC90) is 650 nM. This broadly corresponds to cancer cell data demonstrating high Final, 22 April 2020 14 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) potency of bemcentinib to inhibit AXL. This high potency is reflected in translational data from clinical trials that demonstrate that at the RP2D steady state, AXL kinase is completely inhibited in myeloblasts from AML patients on bemcentinib (Figure 2). Clinically, at RP2D, AXL kinase target demonstrates complete kinase inhibition (Figure 2), thus the maximal possible antiviral effect with this mechanism of action is accessed at the current clinical dose. Clinically, frequent monotherapy complete responses are observed in AML at RP2D (Figure 2). Bemcentinib PK exhibits a prolonged enteral absorptive phase which overlaps with prolonged elimination kinetics after the second dose, to proportionately reduce peak-to-trough difference in plasma concentration-time profile, over a 24-hour dose interval, resulting in smooth steady state without noticeable peak to trough variation (Figure 3). Thus, at the clinical RP2D it is predicted that bemcentinib would be a highly potent antiviral against SARS-CoV-2, and potentially as efficacious as its main use an anticancer therapeutic. Figure 2 Complete Inhibition of AXL Kinase Activation (p-Axl) in Two Acute Myeloid Leukaemia Patients Treated at the Recommended Phase 2 Dose (200 mg Maintenance Daily Dosing) C=cycle; D=day; Pat=patient Final, 22 April 2020 15 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Figure 3 Bemcentinib Plasma Pharmacokinetics in Acute Myeloid Leukaemia Patients Bemcentinib is given orally as 100-mg capsules. Early clinical development in oncology patients identified the RP2D; dose administration of bemcentinib in this study will utilise the same dosing regimen, ie, a loading dose (400 mg) given once daily for 3 days followed by a maintenance dose of 200 mg once daily. Planned duration of bemcentinib treatment is for a total of 15 days, with the possibility of extension to 21 days for in-patients, at the discretion of the clinical investigator. In preclinical and Phase 1 clinical studies, it was shown that systemic exposure to bemcentinib increased dose proportionately. The terminal half-life was 45.6 to 88.7 hours in man. Modelling of the PK data from this study indicated that the most effective approach to rapidly achieving steady state is to administer 3 daily loading doses followed by a lower daily maintenance dose. 2.3 Human Experience from Trials in Cancer Patients Experience has been gained in the use of bemcentinib in the treatment of many types of cancer (including over 286 patients treated with AML, lung cancer, breast cancer, melanoma, and pancreatic cancer) in Phase 2 clinical studies. This has helped to define the safety profile, recommended dose and schedule as a monotherapy (Loges et al 2018). The safety profile of bemcentinib, initially ascertained in normal human volunteers is tolerable and allows monotherapy approaches as well as combinations with chemotherapy (low dose cytosine arabinoside or with docetaxel), targeted therapy (epidermal growth factor receptor inhibitors) and immunotherapy (pembrolizumab). Bemcentinib is given as two oral capsules once daily (200 mg) following three daily 400 mg loading doses, to achieve steady state. Its principal significant AEs are a low incidence of diarrhoea (28% , with 6% Grade 3/4), asymptomatic QT prolongation (6% Grade 3/4), asthenia, and nausea at the RP2D (Loges et al 2018). Many patients have received bemcentinib without untoward effects for over 2 years at full dose. In particular, there were no QTc related cardiac sequelae observed with either monotherapy or combination therapy in over 286 cancer patients, including elderly multimorbid patients (as presented in the Investigator’s Brochure). Evidence of monotherapy efficacy has been Final, 22 April 2020 16 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) documented in heavily pre-treated patients with AML. Complete response rates of approximately 40% have been observed in AXL expressing AML patients (Loges et al 2018), indicating on-target potency and specificity of bemcentinib as a monotherapy, through complete inhibition of the AXL kinase target. Treatment was well tolerated by most subjects, including the frail elderly. Bemcentinib was well tolerated when combined with pembrolizumab, demonstrating synergy with programmed cell death-1 (PD-1) antagonists through targeting of AXL-dependent immune suppressive mechanisms (M2 macrophages, suppressor dendritic cells, regulatory T cells, and myeloid derived suppressor cells). Collectively, bemcentinib mediated activation of innate immunity within the tumour microenvironment synergizes with immune checkpoint therapy (Krebs et al 2019). Final, 22 April 2020 17 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 3.0 STUDY POPULATION 3.1 Eligibility Criteria Overall inclusion and exclusion criteria are presented in Sections 5.1 and 5.2 of the Master Protocol, respectively. Additional exclusion criteria that are specific to the sub-protocol are as follows: 12. Inability to swallow capsules (administration via nasogastric tube is permitted) 13. Current treatment with any agent known to cause QT prolongation. See Appendix 2 for list of relevant medications. The treatment can be discontinued, with sufficient time (5 half-lives) for washout, to allow inclusion of the patient. 14. Screening 12-lead ECG with a measurable QTc interval according to Fridericia correction (QTcF) > 450 ms 15. Clinically significant hypokalaemia. Individuals who do not meet this criterion may be rescreened once. 16. Therapeutic anticoagulation with vitamin K antagonists. Note: Patients receiving low doses prescribed to maintain the patency of venous access devices may be included. 17. Previous bowel resection that would interfere with drug absorption Final, 22 April 2020 18 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 4.0 STUDY ASSESSMENTS AND PROCEDURES In addition to the study assessments and procedures described in Section 8.0 of the Master Protocol, assessments specific to the sub-protocol will be performed as described in the following sections. The Schedule of Activities (SoA) for this sub-protocol is presented in Section 1.2. 4.1 Efficacy Assessments Efficacy assessments will be included as per the Master Protocol. The following endpoints, secondary endpoints in the Master Protocol, will be considered as key secondary endpoints for the purposes of this sub-protocol: Table 1. Bemcentinib Sub-protocol Specific Key Objectives and Endpoints Objectives • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • To evaluate the number of oxygen-free days. • To evaluate ventilator-free days and incidence and duration of any form of new ventilation use. • To evaluate SARS-CoV-2 viral load. • To evaluate SARS-CoV-2 viral load. Endpoints • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29. • Duration (days) of oxygen use and oxygen-free days. • Duration (days) of ventilation and ventilation-free days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 • Qualitative and quantitative PCR determination of SARS-CoV-2 in blood and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 (may be become a secondary endpoint once the assays are available). Exploratory studies will define the role of PD biomarkers. Exploratory endpoints relate to the translational plan. 4.2 Safety Assessments For ECG assessments see the SoA (Section 1.2). Timing of the PK and PD evaluations will be matched to the ECG assessments. Final, 22 April 2020 19 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 4.2.1 Adverse Events 4.2.1.1 Adverse Events from Indications Under Investigation Bemcentinib is a relatively safe investigational therapeutic agent. A few patients may experience tiredness and gastrointestinal disturbance (nausea, diarrhoea). Occasionally there may be some changes to blood tests relating to liver function (transaminitis) and some changes on ECG tracing (QT prolongation). These AEs are temporary and lasting only a few days. 4.2.1.2 Adverse Events of Special Interest (AESI) Not applicable. 4.2.1.3 Disease-related Events and/or Disease-related Outcomes Not Qualifying as Adverse Events or Serious Adverse Events Not applicable. 4.2.2 Clinical Safety Laboratory Assessments See Master Protocol for the list of clinical laboratory tests to be performed for this sub-protocol, and the SoA (Section 1.2) for the timing and frequency. 4.3 Pharmacokinetic Assessments Venous blood samples for PK analysis will be collected according to the SoA (Section 1.2). The samples will be analysed for plasma bemcentinib and additionally for bemcentinib metabolites (to be defined). Detailed procedures for the collection, processing, storage and shipment of the samples will be provided in the Study Laboratory Manual. Plasma samples for determination of bemcentinib concentration will be analysed by BerGenBio’s Bioanalytical Services vendor using the validated liquid chromatography with tandem mass spectrometry method. 4.4 Pharmacodynamic Assessments Blood samples for PD analysis will be collected according to the SoA (Section 1.2) and stored for future analysis in both the bemcentinib arm and the control arm. The samples will be analysed for soluble AXL, GAS6 (which could be predictive, PD, and mechanism biomarkers and hence require comparison with control group not receiving bemcentinib), and other blood proteins. Detailed procedures for the collection, processing, storage and shipment of the samples will be provided in the Study Laboratory Manual. This analysis will be in addition to the inflammatory cytokine analysis detailed in the Master Protocol. Final, 22 April 2020 20 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 5.0 STUDY TREATMENT 5.1 Conclusions and Risk Benefit Statement Bemcentinib has shown in vitro evidence of antiviral effect against SARS-CoV-2 infection at concentrations below those achieved at the proposed dose regimen for use in this trial. This dose matches the RP2D derived from multiple studies in various cancer populations. Treatment at this dose in 286 patients over a range of 6 weeks up to 2 years demonstrates that monotherapy or combination is largely well tolerated; therefore short term administration (15 to 21 days) in the context of hospitalized patients with SARS-CoV-2 infection is anticipated to be well tolerated. A non-severe, asymptomatic effect on QTc interval has been noted. Regular ECG/continuous ECG monitoring is included in the clinical trial enabling early identification of prolonged QTc and early stopping rules given the high morbidity and potential mortality of SARS-CoV-2 in hospitalised patients, there is a favourable balance of potential benefit: risk in the proposed clinical investigation of bemcentinib treatment for COVID-19 within the context of this clinical trial. 5.2 Bemcentinib Drug Administration Bemcentinib will be administered as a 400 mg oral loading dose on Days 1, 2, and 3, followed by 200 mg once-daily oral maintenance dose for 15 days with the possibility of extension to 21 days for in patients at the discretion of the clinical investigator. Bemcentinib should be taken once per day, in the morning after an overnight fast. Tablets should be taken with 100 mL water. Patients should not consume anything other than water for at least 1 hour after taking study drug. Final, 22 April 2020 21 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 5.3 Dose Modifications and Toxicity Management Note: this modified guidance has been added to the Investigators’ Brochure under relevant section of treatment of COVID-19 Event Recommended Bemcentinib Dose Modification Estimated creatinine clearance decreases Study medication should be withheld until estimated creatinine by more than ≥50% from baseline clearance returns to baseline ALT or AST increases to > 5 ULN Study medication should be withheld until ALT and AST returns to baseline Dose Modification of Bemcentinib Daily Dose for QTc Prolongation QTcF Recommended Bemcentinib Dose Modification > 501 ms 1st occurrence Discontinue permanently Ventricular arrhythmia 1st occurrence Discontinue permanently ALT=alanine aminotransferase; AST=aspartate aminotransferase; QTcF= QTc interval according to Fridericia correction; ULN=upper limit of normal Notes: Serum calcium, magnesium and potassium should be measured regularly whilst receiving bemcentinib; all abnormal results should be corrected; check for use of concomitant medication that are associated with QT prolongation. 5.4 Prohibited Concomitant Medications Administration of bemcentinib is contraindicated in patients requiring treatment with concomitant medications known to prolong QTc interval and promote Torsade de Points (TdP) listed in Appendix 2. Patients already in receipt of such medications should be excluded unless medications are discontinued and a sufficient wash out period is allowed prior to starting bemcentinib. Medicines with both cytochrome P450 (CYP) 3A4 and TdP liabilities are particularly hazardous and their concomitant use is a reason for exclusion of patients. Concomitant medications that are CYP3A4 substrates are not reasons for exclusion of patients, however they should be discontinued or used with caution. Treatment with histamine receptor 2 inhibitors (cimetidine, ranitidine) or protein pump inhibitors (omeprazole) is permitted provided that administration is in the evening. 5.5 Study Drug Information 5.5.1 Study Medication The drug product is presented in a single strength: 100 mg bemcentinib in size 0, Swedish Orange hydroxypropyl methylcellulose capsules for oral administration. Bemcentinib capsules Final, 22 April 2020 22 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) consists of a wet granulated blend of 40% drug substance with standard excipients (lactose monohydrate, microcrystalline cellulose, crospovidone, polyvinylpyrrolidone, colloidal silicon dioxide, and magnesium stearate). Bemcentinib has been manufactured according to appropriate Good Manufacturing Practice standards. Bemcentinib capsules are packaged in 50-mL white opaque round high density polyethylene bottles containing 22 capsules. The bottles are closed with opaque 32-mm child-resistant screw caps and sealed with tamper-resistant tape. Refer to the current version of the Bemcentinib Investigational Medicinal Product Dossier/Investigator’s Brochure for additional information on the physical, chemical and pharmaceutical properties of bemcentinib. 5.5.2 Bemcentinib Storage, Dispensing, and Destruction Bemcentinib will be shipped to the participating site by PCI Pharma Services, UK, and must be stored at the site in a secure location under ambient temperature conditions (<25°C). Accountability for study treatment is the responsibility of the Investigator. The Investigator/designee must ensure that the bemcentinib will only be dispensed to patients in accordance with the dosing instructions in this protocol. Study staff should refer to the Bemcentinib Pharmacy Manual for specific instructions regarding the handling, storage, dispensing and destruction of bemcentinib. Final, 22 April 2020 23 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 6.0 REFERENCES Bhattacharyya S, Zagórska A, Lew ED, et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 2013;14:136-47. Brindley MA, Hunt CL, Kondratowicz AS, et al. Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein. Virology 2011;415:83-94. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell 2016;19:181-93. Chen J, Yang YF, Yang Y, et al. AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling. Nat Microbiol 2018;3(3):302-9. Dong N, Yang X, Ye L, Chen K, Chan EW, Chen S. Genomic and protein structure modelling analysis depicts the origin and pathogenicity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China [version 2; peer review: 1 not approved]. F1000Research 2020, 9:121 (https://doi.org/10.12688/f1000research.22357.2) Dowall SD, Bewley K, Watson RJ, et al. Antiviral Screening of Multiple Compounds against Ebola Virus. Viruses 2016;8(11). pii:E277. Hastings AK, Hastings K, Uraki R, et al. Loss of the TAM Receptor Axl Ameliorates Severe Zika Virus Pathogenesis and Reduces Apoptosis in Microglia. iScience 2019;13:339-50. Huang MT, Liu WL, Lu CW, et al. Feedback regulation of IFN-αβ signalling by Axl receptor tyrosine kinase modulates HBV immunity. Eur. J. Immunol. 2015;45:1696-705. Krebs M et al. A phase II study of bemcentinib (BGB324), a first-in- class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC: Updated analysis. SITC 2019, oral presentation in High Impact Clinical Trials session. Lemke G. How macrophages deal with death. Nat Rev Immunol. 2019;19(9):539-49. Loges S et al. Comprehensive Analysis of the Dose Escalation, Expansion and Correlates in the Ph I/II Trial BGBC003 with the Selective Oral AXL Inhibitor Bemcentinib (BGB324) in Relapsed/Refractory AML and MDS ASH 2018, presentation. Lokugamage KG, Hage A, Schindewolf C, Rajsbaum R, Menachery VD. SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv preprint doi: https://doi.org/10.1101/2020.03.07.982264.Meertens L, Carnec X, Lecoin MP, et al. The TIM Final, 22 April 2020 24 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus Entry. Cell Host Microbe 2012;12(4):544-57. Meertens L, Labeau A, Dejarnac O, et al. Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell Rep 2017;18(2):324-33. Mercer J, Helenius A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 2008;320(5875):531-5. Shibata T, Habiel DM, Coelho AL, Kunkel SL, Lukacs NW, Hogaboam CM. Axl Receptor Blockade Ameliorates Pulmonary Pathology Resulting from Primary Viral Infection and Viral Exacerbation of Asthma. J Immunol. 2014;192(8):3569-81. Shimojima M, Takada A, Ebihara H, et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006;80(20):10109-16. Strange DP, Jiyarom B, Pourhabibi Zarandi N, et al. Axl promotes Zika virus entry and modulates the antiviral state of human Sertoli cells. mBio 2019;10(4):e01372-19. Final, 22 April 2020 25 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) 7.0 APPENDICES Appendix 1 Abbreviations Abbreviation ACE AE AML BP CYP EBOV ECG GAS6 IC50 IC90 IFN IL MHV NK NYHA PD PD-1 PK PS QTcF RP2D RSV SARS SARS-CoV-2 SoA SOCS TAM TdP Definition Angiotensin-converting enzyme Adverse event Acute myeloid leukaemia Blood pressure Cytochrome P450 Ebola virus Electrocardiogram Growth arrest-specific 6 Half maximal inhibitory concentration Concentration required for 90% of maximum inhibition Interferon Interleukin Mouse hepatitis virus Natural killer New York Heart Association Pharmacodynamic Programmed cell death-1 Pharmacokinetic Phosphatidylserine QTc interval according to Fridericia correction Recommended Phase 2 dose Respiratory syncytial virus Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Schedule of Activities Suppressor of cytokine signalling Tyro3, AXL, MerTK Torsade de Points Final, 22 April 2020 26 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Appendix 2 Prohibited Concomitant Medication Due to QT Prolongation Risk or CYP3A4 Interaction with Narrow Therapeutic Index For any concomitant medication, please check the following website for the drug’s Torsades de Pointes (TdP) risk: https://crediblemeds.org/oncosupport/. Drugs with known (TdP) risk are reason for EXCLUSION. For drugs with a conditional risk, please review the product label and correct any abnormalities, eg, hypokalaemia. Common medication Associated with a Risk of QT Prolongation and TdP – USE PROHIBITED AS CONCOMITANT MEDICATION t½ less than 6 hours Azithromycin 2-4 hours$ Clarithromycin 3-4 hours$ Cocaine 0.6 – 1.3 hours$ Droperidol 2 hours$ Erythromycin 2 hours$ Ondansetron 3 hours$ Procainamide 2.5-4.75 hours$ Terfenadine 3.5 hours** t½ between 6 – 12 hours Cisapride 10 hours ** Disopyramide 6.7 hours$ Ketoconazole 3 – 10 hours$ Moxifloxacin 12 hours$ Quinidine 6 hours **$ Voriconazole 6 hours$ t½ greater than 12 hours Amiodarone 50 days$ Astemizole 24 hours ** Chloroquine 1-2 months$ Citalopram 35 hours$ Escitalopram 30 hours$ Fluconazole 30 hours$ Haloperidol 15 – 27 hours$ Methadone 25 – 55 hours$ Petamidine 10 – 14 days$ **also CYP3A4 substrates $ also TdP risk Pimozide 55 hours ** Sotalol 10 – 20 hours$ Thioridazine 21 – 24 hours$ Sensitive CYP3A4 Substrates With A Narrow Therapeutic Margin THESE MEDICATIONS SHOULD BE DISCONTINUED BEFORE ENROLMENT t½ less than 6 hours t½ between 6 – 12 hours t½ greater than 12 hours alfentanyl 90-111 minutes dihydroergotamine & ergotamine 2 hours Fluticasone 3 – 8hours Terfenadine 3.5 hours astemizole 7 – 9 hours cisapride 12 hours cyclosporine 8.4 hours Fentanyl 8 – 10 hours quinidine 6 hours tacrolimus (FK506) 12 hours pimozide 55 hours sirolimus 63 hours Woosley RL, Heise CW , Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, QTdrugs List, [14Apr2020], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755 Final, 22 April 2020 27 CONFIDENTIAL ACCORD-2-002 - Sub protocol for Bemcentinib (Amendment 01) Appendix 3 Signature of Investigator PROTOCOL TITLE: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients SUB-PROTOCOL NO: ACCORD-2-002 SUB-PROTOCOL FOR CANDIDATE AGENT BEMCENTINIB VERSION: Amendment 01 This sub-protocol is a confidential communication of the Sponsor. I confirm that I have read this sub-protocol, I understand it, and I will work according to this sub-protocol, in conjunction with the Master Protocol for the overall platform study. I will also work consistently with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and the applicable laws and regulations. Acceptance of this document constitutes my agreement that no unpublished information contained herein will be published or disclosed without prior written approval from the Sponsor. Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study centre in which the study will be conducted. Return the signed copy to the Contract Research Organization/Sponsor. I have read this sub-protocol in its entirety and agree to conduct this part of the study accordingly: Signature of Investigator: Printed Name: Investigator Title: __________________________ ___________________________ ___________________________ Date: ________ Name/Address of Centre: ___________________________ ___________________________ ___________________________ Final, 22 April 2020 28
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Children's allergy clinic - patient information

Description
We have given you this factsheet to give you more information about our allergy clinic and the service we provide at Southampton Children's Hospital (SCH).
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/Media/UHS-website-2019/Patientinformation/Childhealth/Childrens-allergy-clinic-2431-PIL.pdf

Key research funders_remit_Nov2019

Description
Key research funders – their focus and philosophies UKRI – UK Research and Innovation Launched in April 2018 and with a £7bn budget, UKRI brings together the seven Research Councils, Innovate UK and Research England (formerly HEFCE) to support world-leading research and innovation and create the optimal environment for research and innovation to flourish. Funded primarily through the Department for Business, Energy and Industrial Strategy (BEIS), UKRI aspires to: ? Push the frontiers of human knowledge and understanding ? Deliver economic impact and prosperity ? Create social and cultural impact UKRI works in partnership with universities, research organisations, businesses, charities and government. UKRI is seen as a key vehicle to help the government reach its target of increasing investment in R&D to 2.4% of GDP by 2027. UKRI funding will be delivered through a combination of traditional routes through the separate Councils, and a number of centrally held pots of money, a few of which are detailed below. ? UKRI Future Leaders Fellowships – this scheme aims to develop, retain, attract and sustain research and innovation talent in the UK. Providing up to seven years of funding, the scheme will tackle difficult and novel challenges. There are two calls each year. ? Strategic Priorities Fund – for high quality multi- and interdisciplinary research and innovation programmes. Groups of Councils bid into UKRI around a specific area, and if successful, a call is announced through a lead Council. ? Strength in Places Fund – this new, competitive scheme takes a place-based approach to growth through Research and Innovation. The scheme looks at clusters of businesses within a region that have the potential to innovate or adopt new technology, and to enhance local collaborations of research and innovation. ? Global Challenges Research Fund - a £1.5 billion fund announced by the UK Government in late 2015 to support cutting-edge research projects that address the challenges faced by developing countries. Funding is allocated in a mixed of internal competitions and in response to arising opportunities or challenges. The University of Southampton leads these applications. ? Fund for International Collaboration – aims to enhance the UK’s research and innovation through global engagement via bilateral and multilateral programmes. This fund of around £110m is delivered through the UKRI Councils. ? Turing Artificial Intelligence (AI) Acceleration Fellowship and Turing AI World-Leading Fellowship will open in November. The University of Southampton leads these applications. www.ukri.org MRC – Medical Research Council The MRC supports research across the full spectrum of medical science from laboratory research to clinical trials and population studies. It also provides career awards for scientists. Funding opportunities are either researcher-led or aligned to an area strategic to the MRC. The delivery plan focuses on four areas: ? Discovery science ? Investing in people ? Fostering collaboration Key research funders_remit_Nov2019 ? New technologies and infrastructure Underpinning this, seven priority health themes have been identified in their strategy: ? Prevention and early detection ? Precision medicine ? Multi-morbidities ? Advanced therapies ? Mental health ? Antimicrobial resistance ? Global health www.mrc.ukri.org BBSRC – Biotechnology and Biological Sciences Research Council Focuses on supporting discovery research, transformative technologies and researcher development: ? Advancing the frontiers of bioscience discovery ? Understanding the rules of life ? Transformative technologies ? Tackling strategic challenges ? Bioscience for sustainable agriculture and food ? Bioscience for renewable resources and clean growth ? Bioscience for an integrated understanding of health ? Building strong foundations ? People and talent ? Infrastructure ? Collaboration, partnerships and knowledge exchange Funding opportunities exist through doctoral training, leadership and responsive mode research grants. www.bbsrc.ukri.org Other Research Councils AHRC – Arts and Humanities www.ahrc.ukri.org EPSRC – Engineering and Physical Sciences www.epsrc.ukri.org ESRC – Economic and Social www.esrc.ukri.org NERC – Natural Environment www.nerc.ukri.org STFC – Science and Technology Facilities Council www.stfc.ukri.org Innovate UK Part of UKRI, Innovate UK drives productivity and economic growth by supporting businesses to develop and realise the potential of new ideas. It funds business and research collaborations, accelerating innovation and commercialisation. Five strategic goals are laid out in the Delivery Plan 2019: 1. Deliver measurable economic and societal impact across the UK 2. Support and invest in innovative businesses and entrepreneurs with the potential and ambition to grow Key research funders_remit_Nov2019 3. Maximise the commercial impact of world-class knowledge developed in UK industries and its research base 4. Identify, support and grow transforming and emerging industries through innovation 5. Build a coherent, supportive environment incentivising R&D investment and enabling people and businesses to innovate Priority Areas for Investment: ? Artificial intelligence (AI) and the data economy ? Ageing society, health and nutrition ? Clean growth and infrastructure ? Mobility, manufacturing and materials https://www.gov.uk/government/organisations/innovate-uk NIHR – National Institute for Health Research Established in 2006, the NIHR is the nation’s largest funder of health and care research and works in partnership with the NHS, universities, local government, other research funders, patients and the public. Its central mission is to improve the health and wealth of the national through research. This is delivered by fiver strategic workstreams: ? Funding, supporting and delivering high quality research ? Engaging and involving patients, carers and the public ? Attracting, training and support the best researchers ? Investing in world class infrastructure and a skilled delivery workforce ? Partnering with other public funders, charities and industry Ten programmes address different research areas, methodologies and scales. In addition, the NIHR Academy delivers career support and advice, access to leadership development opportunities, mentoring and guidance through a range of training awards for all healthcare professionals. Many schemes are open cyclically, providing regular opportunities for making applications at times to suit career and project trajectories. www.nihr.ac.uk Wellcome Trust The Wellcome Trust directly funds scientists and researchers around the world at every step from discovery to impact through grants for research project and career development. Grants are available across biomedical sciences, population health, medical innovation, humanities and social science, and public engagement. Wellcome focusses funding in areas where it can lead significant change within five to ten years, such as drug-resistant infections; vaccines; mental health; epidemics; and data science and innovation. https://wellcome.ac.uk/funding Details of other funders can be found on the current funding calls web page Key research funders_remit_Nov2019
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/Media/Southampton-Clinical-Research/Grants/Download/Key-research-funders-remit-Nov2019.pdf

Procedure for adult DXA

Description
NIHR Southampton Biomedical Research Centre The NIHR Southampton Biomedical Research Centre (BRC) has a tight quality assurance system for the writing, reviewing and updating of Standard Operating Procedures. As such, version-controlled and QA authorised Standard Operating Procedures are internal to the BRC. The Standard Operating Procedure from which information in this document has been extracted, is a version controlled document, managed within a Quality Management System. However, extracts that document the technical aspects can be made more widely available. Standard Operating Procedures are more than a set of detailed instructions; they also provide a necessary record of their origination, amendment and usage within the setting in which they are used. They are an important component of any Quality Assurance Framework, but in themselves are insufficient and need to be used and interpreted with care. Alongside the extracts from our Standard Operating Procedures, we have also made available here an example Standard Operating Procedure and a word version of a Standard Operating Procedure template. Using the example and the Standard Operating Procedure template, institutions can generate their own Standard Operating Procedures and customise them, in line with their own institutions. Simply offering a list of instructions to follow does not assure that the user is able to generate a value that is either accurate or precise so here in the BRC we require that Standard Operating Procedures are accompanied by face-to-face training. This is provided by someone with a qualification in the area or by someone with extensive experience in making the measurements. Training is followed by a short competency assessment and performance is monitored and maintained using annual refresher sessions. If you require any extra information, clarification or are interested in attending a training session, please contact Dr Kesta Durkin (k.l.durkin@soton.ac.uk). This document has been prepared from Version 1 of the BRC Standard Operating Procedure for performing DXA on adults. It was last reviewed in September 2015 and the next review date is set for September 2017. The version number only changes if any amendments are made when the document is reviewed. Page 1 of 4 NIHR Southampton Biomedical Research Centre NIHR Southampton Biomedical Research Centre Procedure for PERFORMING ADULT DXA (Body Composition) BACKGROUND This procedure is to be used for Dual-energy X-ray Absorptiometry (DXA) scans. DXA scanning, also called bone density scanning, DEXA or bone densitometry, is an enhanced form of radiographic technology that is used to measure bone loss, bone mineral accrual and body composition. DXA is today's established standard for measuring bone mineral density (BMD). A radiograph is a painless medical test that helps physicians diagnose and treat medical conditions. In addition to assessment of BMD, DXA measures fat content and non-fat non-bone tissue. At the whole body site, this permits accurate assessment of body composition. PURPOSE To ensure patient safety and correct preparation and conduct for whole body DXA scanning of adults. SCOPE This procedure applies to any study involving whole body DXA scanning of adults within the BRC. RESPONSIBILITIES It is the responsibility of the measurer to read and follow this procedure when carrying out DXA scanning of adults within the BRC. It is the responsibility of the principle investigator to ensure that staff members who are working on specific studies have adequate experience and are competent to do so. Page 2 of 4 NIHR Southampton Biomedical Research Centre PROCEDURE The system used is a Hologic Discovery DXA System, manufactured by Hologic Inc.. In the UK servicing, updates and repairs are supported by Vertec Ltd. www.vertec.co.uk Contraindications to scanning ? ? ? Pregnancy. Any investigation carried out in the last 10 days using a radioisotope, as these will affect the body composition results. Presence of internal metal artefacts, as these will affect the body composition results. 1. 2. 3. Ensure that the patient has removed all jewellery and is not wearing clothing with buckles, belts or metal fasteners. Ensure that the patient is positioned to move to and from the table with the scan arm to the left (foot-end) of the table, for stability and access. Ensure that the patient is lying on his/her back with their head at the right end of the table and that they are positioned within the scan limit borders marked on the mattress. The feet of taller patients may have to hang over the edge of the bed. Ask the patient to place their arms by their sides with their palms facing downwards but not touching their thighs. This might be difficult to achieve in large/obese patients, in which case their arms should be by their sides with palms touching their thighs. Ensure that the patient's feet are rotated slightly inwards, leaving a gap between the toes. If movement may be a problem, thin tape may be placed around the toes to support the legs in position. Ask the patient to breathe normally and keep as still as they can. Scanning is started in accordance with the operating procedure detailed in the Hologic Discovery Training Manual. The operator should inform the patient that they need to keep as still as possible until the scan arm has completed 7 passes of their body. Explain that this should take approximately 7.5 minutes. The DXA machine is operated using the settings and techniques described in the Hologic Discovery training Manual, which is stored in the scan room. The scan is then analysed using the Whole Body Fan Beam analysis algorithm and the results are printed. 4. 5. 6. 7. 8. 9. 10. Page 3 of 4 NIHR Southampton Biomedical Research Centre The equipment is calibrated with quality control checks using a spine phantom before every use by appropriately qualified and trained staff. In addition, a weekly step-wedge check is performed for system accuracy. The machine will not operate if these checks are not passed. The staff will use the equipment in accordance with specified guidelines produced by the manufacturer and will be qualified in radiation protection procedures. Only the volunteers are exposed to ionising radiation (x-rays) during the procedure and the approximate radiation doses are recorded in the patient's hospital notes. Page 4 of 4
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/Media/Southampton-Clinical-Research/Procedures/BRCProcedures/Procedure-for-adult-DXA.pdf
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