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Secondary breast care services in Wessex region

Description: Wessex Clinical Genetics Service G level, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA Tel 023 8120
Url: /Media/UHS-website-2019/Docs/Services/Genetics/Cancer-genetics/secondary-breast-care-services-in-wessex-region.docx

Post-enucleation socket syndrome (PESS) - patient information

Description: This factsheet contains information about post-enucleation socket syndrome (PESS).
Url: /Media/UHS-website-2019/Patientinformation/Eyes/Post-enucleation-socket-syndrome-PESS-3169-PIL.pdf

DH IVIg approved indications full guidance July 2011

Description: DH INFORMATION READER BOX Policy HR / Workforce Management Planning / Clinical Performance Document Purpose Gateway Reference Title Author Publication Date Target Audience Estates Commissioning IM & T Finance Social Care / Partnership Best Practice Guidance 16290 ROCR Ref: ROCR approval applied for Clinical guidelines for immunoglobulin use: update to second edition Department of Health 01 Aug 2011 PCT CEs, NHS Trust CEs, SHA CEs, Foundation Trust CEs , Medical Directors, Directors of Finance, GPs, Communications Leads, Emergency Care Leads, Chief Pharmacists Circulation List #VALUE! Description The Clinical Guidelines for Immunoglobulin Use were implemented in 2008. The Guidelines were developed utilising an evidence review and extensive consultations. This Update fulfills the commitment to undertake a biennial review from 2009. The Second Edition Guidelines remain in place and this Update should be used in conjunction with them. Cross Ref Superseded Docs Action Required Timing Contact Details Clinical Guidelines for Immunoglobulin Use (Second Edition) N/A N/A N/A Tina Lee Blood Safety & Supply Team Room 30 Wellington House 133-155 Waterloo Road London SE1 8UG 020 7972 4750 0 For Recipient's Use Clinical guidelines for IMMUNOGLOBULIN Use seCOND eDITION UPDATe second edition Update Working Group Dr Jennie Wimperis Consultant Haematologist, Norfolk and Norwich NHS Trust Dr Michael Lunn Consultant Neurologist, National Hospital for Neurology and Neurosurgery Dr Alison Jones Consultant Immunologist, Great Ormond Street Hospital Dr Richard Herriot Consultant Immunologist, NHS Grampian Dr Philip Wood Consultant Immunologist, Leeds Teaching Hospitals NHS Trust Dr Denise O'shaughnessy Blood Policy, Department of Health Mr Malcolm Qualie Pharmaceutical Advisor Department of Health CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Contents ...................................................................................... 2 eXeCUTIVe sUMMARY ....................................................................... 6 Selection criteria for appropriate use of immunoglobulin .................................. 6 Efficacy outcomes to assess treatment success ........................................... 6 Modification of existing indications and inclusion of new indications .................... 7 Commissioning of immunoglobulin ........................................................... 7 INTRODUCTION ................................................................................ 8 Insights from the National Immunoglobulin Database ..................................... 8 CONTeNTs Changes to the colour-coded prioritisation employed in the Demand Management Programme ...................................................................... 8 Automatic assignment of Red and Blue prioritisation ................................. 9 Grey indications ............................................................................. 9 Reclassification of diseases .............................................................. 10 11 12 12 13 14 14 14 15 16 18 26 27 27 Introduction of specific selection and outcome criteria in the Demand .................................................................... Definitions of duration of immunoglobulin treatment ..................................... Recommended dosing of immunoglobulin ................................................ Ideal body weight-adjusted dosing of immunoglobulin .................................. Western Australia pilot study ............................................................. Hospital Corporation of America ........................................................ The Ohio State University Medical Centre, Columbus, Ohio ........................ Infusion rates for intravenous immunoglobulin ............................................ Subcutaneous administration ............................................................... sUMMARY TABLes .......................................................................... sUMMARY Of GReY INDICATIONs ...................................................... Removed from Grey ........................................................................... INDICATIONs fOR WHICH IVIG Is NOT ReCOMMeNDeD .......................... Management Programme CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Replacement pages IMMUNOLOGY HAeMATOLOGY ............................................................................... .............................................................................. 29 35 Primary immunodeficiencies (replacing relevant content on pages 28-29) Coagulation factor inhibitors (replacing relevant content on pages 32-33) Haemolytic disease of the foetus and newborn (replacing relevant content on pages 32-33) Immune thrombocytopenic purpura (replacing relevant content on pages 34-35) NeUROLOGY ................................................................................. 40 Introduction (replacing relevant content on page 41) Chronic inflammatory demyelinating polyradiculoneuropathy (replacing relevant content on page 41) Inflammatory myopathies (replacing relevant content on page 42) TRANsPLANTATION ........................................................................ 43 Antibody Incompatible Transplant (AIT) (replacing relevant content on page 65) Antibody-Mediated Rejection (AMR) (replacing relevant content on page 65) Viral pneumonitis (replacing relevant content on page 65) CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Summary table of conditions for which intravenous immunoglobulin use is appropriate Condition Primary and secondary antibody deficiency states Primary immunodeficiencies Thymoma with immunodeficiency HSCT in primary immunodeficiencies Specific antibody deficiency Secondary antibody deficiency (any cause) Haematology Acquired red cell aplasia Alloimmune thrombocytopenia (foeto-maternal/neonatal) Autoimmune haemolytic anaemia Coagulation factor inhibitors (alloantibodies and autoantibodies) Haemolytic disease of the newborn Haemophagocytic syndrome Immune thrombocytopenic purpura (acute and persistent, excluding chronic*) Post-transfusion purpura Neurology Chronic inflammatory demyelinating polyradiculoneuropathy** Guillain-Barr? syndrome Inflammatory myopathies Myasthenia gravis (including Lambert-Eaton myasthenic syndrome) Multifocal motor neuropathy Paraprotein-associated demyelinating neuropathy (IgM, IgG or IgA) Rasmussen syndrome Stiff person syndrome short duration Long duration continued * Chronic immune thrombocytopenic purpura is a grey indication ** The disease should be life-threatening to allow database entry as red CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Summary table of conditions for which intravenous immunoglobulin use is appropriate continued Condition Others Autoimmune congenital heart block Autoimmune uveitis Immunobullous diseases Kawasaki disease Necrotising (PVL-associated) staphylococcal sepsis Severe or recurrent Clostridium difficile colitis Staphylococcal or streptococcal toxic shock syndrome Toxic epidermal necrolysis, Stevens Johnson syndrome Transplantation (solid organ) short duration Long duration CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use eXeCUTIVe sUMMARY The Clinical Guidelines for Immunoglobulin Use were implemented in 2008. The Guidelines were developed utilising an evidence review and extensive consultations with clinicians and other stakeholders. This update fulfils the commitment made in the Second Edition to undertake a biennial review from 2009. The Second Edition Guidelines remain in place and this update should be used in conjunction with the Second Edition. This update did not review all of the Second Edition Guidelines content, but limited its focus to three key areas: defining selection criteria for appropriate use; efficacy outcomes to assess treatment success; and reassignment of existing indications /inclusion of new indications. should be fulfilled if immunoglobulin is to be used, including particular disease characteristics, disease severity and any requirement for other treatments to have been demonstrably unsuccessful before immunoglobulin is considered. This reflects the approach taken by the National Blood Authority in Australia in defining appropriate prescribing of immunoglobulin. efficacy outcomes to assess treatment success The Guidelines did not include efficacy tracking of immunoglobulin treatment, although Immunoglobulin Assessment Panels (IAP) were encouraged to request parameters by which efficacy could be assessed. This update provides efficacy outcomes to be measured in all indications (except primary immunodeficiencies), and it is expected that all Grey indications will have efficacy parameters defined and monitored on a case by case basis. Efficacy outcomes are expected to play an important role in the IAP decision-making process for patients in whom continuation of immunoglobulin treatment is requested beyond the short- and long-term durations defined in this update. This change reflects the wider change of focus in the NHS to patient outcomes, as presented in The NHS Outcomes Framework. selection criteria for appropriate use of immunoglobulin The Guidelines did not provide explicit selection criteria for the appropriate use of immunoglobulin. Review of data in the National Immunoglobulin Database showed a considerable volume of immunoglobulin was used in patients for whom no specific diagnosis was provided. Clearly, this was less than optimal and caused concern among commissioners. This update provides criteria that CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Modification of existing indications and inclusion of new indications Changes to existing indications required proponents to submit new evidence to the Update Working Group for review. However, allocation of diseases to Red, Blue or Grey did not solely depend on the level of evidence presented, but included expert clinical advice and the availability of effective alternative therapies or treatment approaches. The British Transplantation Society made a strong case to change certain defined transplant cases to Blue, despite limited high-quality evidence for some of the clinical scenarios and the Update Working Group accepted the Society's view. For complex regional pain syndrome, although randomised evidence from a small study showed benefit, this was regarded by the Update Working Group as an emerging indication for refractory cases; a number of important questions concerning optimal treatment doses and duration of treatment remain unanswered. Therefore, this disease has been added to the Grey list. It remains the responsibility of the local IAP to decide with the PCT (or specialised commissioning group) if treatment with immunoglobulin is appropriate on a case by case basis. Other Grey indications have been updated and others, for which there was little or no prescribing recorded in the database, deleted. Grey indications are now listed as immune-mediated disorders with limited evidence of immunoglobulin efficacy, or presumed immune-mediated disorders with little or no evidence of efficacy. Review of Red and Blue indications identified a number of disease entities with the same underlying pathophysiology that were listed separately; these are now grouped together under single disease headings. Commissioning of immunoglobulin Ensuring immunoglobulin prescribing is consistent with the evidence-base and restricted to those patients for whom there are no alternative treatments and for those most likely to benefit is the central aim of these guidelines. But from a commissioner's viewpoint, cost-effectiveness and affordability play an important role in their discussions with IAPs regarding prescribing. The commissioning aspects of this guideline update are included in a separate document and this should be reviewed to understand the requirements of commissioners around immunoglobulin prescribing, in particular regarding National Immunoglobulin Database entry and treatment duration. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use INTRODUCTION This update of the Department of Health's (DH) immunoglobulin guidelines fulfils the commitment made in the Second Edition to undertake a biennial review from 2009. This review was informed by changes in the clinical evidence base for immunoglobulin, the findings of the National Immunoglobulin Database (Reference number ROCR/ OR/0221), and a change of focus in the NHS to patient outcomes, as presented in The NHS Outcomes Framework. The DH has consulted widely in this review and the changes have been discussed at length with clinicians and commissioners involved in the demand management of immunoglobulin. National Immunoglobulin Database was launched on 2nd June 2008. These documents and the National Immunoglobulin Database are accessible through the immunoglobulin website www.ivig.org.uk. The first data review from the National Immunoglobulin Database, published in January 2010, contained data on immunoglobulin prescribing in 5119 patients, and offered a unique, detailed view of prescribing practice of immunoglobulin in England as well as providing, for the first time, a baseline of immunoglobulin use. This was a major step forward in establishing the Demand Management Programme and, in particular, gave insights into the appropriate use of this treatment across all indications. Generally, the data demonstrated appropriate and controlled prescribing of immunoglobulin for a wide range of conditions, most of which was evidence based. The review also identified a number of issues regarding the Demand Management Programme, which are addressed in this guideline update. Insights from the National Immunoglobulin Database The DH's Demand Management Programme for Immunoglobulin was a key output from the 2006 review that assessed the opportunities available to secure the supply of immunoglobulin. The review recommended two complementary work streams, one based on securing supply and the other giving structure to the process of fulfilling demand (the Demand Management Programme). The Demand Management Programme was fully launched in late May 2008, when DH published the Second Edition of `Clinical Guidelines for Immunoglobulin Use' and the `Demand Management Plan for Immunoglobulin Use' (Gateway reference 10012 and 10013). The Changes to the colour-coded prioritisation employed in the Demand Management Programme Automatic assignment of Red and Blue prioritisation The Demand Management Programme introduced colour coding to reflect the prioritisation of immunoglobulin treatment CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use in times of shortage, based on the availability of alternative treatments and strength of clinical evidence. The database review showed many cases for which diseases were mis-assigned to an incorrect prioritisation. In particular, there were many cases of misassignment of diseases to Red and Blue. `Red' indicates conditions for which treatment is considered the highest priority because of a risk to life without treatment. The intention remains that Trusts will protect supply for these high-priority diseases in times of immunoglobulin shortage, particularly for patients with primary immunodeficiencies. To ensure accurate prioritisation assignment, the database will now automatically assign the colour coding upon patient entry on the basis of patient characteristics. The Immunoglobulin Assessment Panels (IAP) at Trusts should continue to manage local demand for immunoglobulin; in times of shortage, local panels should continue to identify Red indications as those of most clinical need. The database will automatically assign diseases to `Blue', but prescribing of immunoglobulin in Blue indications will continue to require prior approval of the IAP . because the disease is rare. Approval from both the local IAP and the Primary Care Trust (PCT) (or specialised commissioning group) is required for immunoglobulin treatment. As previously specified in the Demand Management Plan for Immunoglobulin Use, treatment should be considered on a caseby-case basis, and prioritised against other competing demands for immunoglobulin, especially in times of shortage. It is not possible or desirable to list every disease that could potentially be prescribed immunoglobulin. In cases of `unlisted' diseases, it is important to restate that those not listed in the guidelines are to be considered as Grey. The database review showed a considerable volume of immunoglobulin prescribed without a specific diagnosis being provided. Even if the disease is unlisted, the diagnosis and agreed efficacy criteria are to be recorded in the database. Grey indications are now listed as immune-mediated disorders with limited evidence of immunoglobulin efficacy, or presumed immune-mediated disorders with little or no evidence of efficacy. It is accepted that the lack of an evidence base may reflect the rarity of these diseases; it remains the responsibility of the local IAP to decide with the PCT (or specialised commissioning group) if treatment with immunoglobulin is appropriate on a caseby case basis. Grey indications `Grey' indications are those diseases for which the evidence is weak, in many cases 10 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Reclassification of diseases 1. Grey to Blue The database review identified two of the top 10 immunoglobulin-using indications as Grey (secondary antibody deficiencies and antibody-mediated rejection following solid organ transplantation). In many Trusts, commissioners have permitted pre-approval of immunoglobulin use for these indications despite the limited evidence base. Therefore, these indications were reviewed in detail and the evidence base was reassessed. Secondary antibody deficiencies were identi- Acquired von Willebrand disease has now been included with acquired haemophilia, in the general disease grouping of `Coagulation factor inhibitors', which is listed under appropriate use of immunoglobulin. Immunoglobulin use carries selection criteria, including that these rare and severe bleeding disorders are managed in a comprehensive care centre for haemophilia. Polymyositis and Inclusion body myositis have now been grouped with dermatomyositis under the general disease grouping of inflammatory myopathies, with strict selection criteria. Post-transfusion hyperhaemolysis has now been fied by a number of stakeholders as a key area for revision. In the previous edition, they were listed under immunosuppressive pharmacotherapy, and separately under some of the haematological malignancies such as CLL, without listing other mature B-cell malignancies such as non-Hodgkin's lymphoma. These have been revised into a single indication. The outcome of this review is that use of immunoglobulin for these indications is appropriate and is now listed as Blue (see replacement page 30). Antibody-mediated rejection following solid grouped under the more general heading of haemolytic anaemia. SLE with secondary immunocytopenias should be considered under the relevant immune cytopenia. 2. Blue to Red Specific antibody deficiency, as a recognised primary antibody deficiency disorder, has been reclassified as a Red indication (for those cases where immunoglobulin replacement therapy is required). Haemolytic disease of the newborn has been organ transplantation and antibody-incompatible transplantation were reviewed, and a single grouping of `Transplantation (solid organ)' has been introduced and listed as Blue. updated to reflect recommendations in NICE clinical guideline 98 on neonatal jaundice [1]. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 11 Introduction of specific selection and outcome criteria in the Demand Management Programme Selection criteria The database review also raised an important issue over patient diagnosis ? a considerable volume of immunoglobulin was used in patients in which there was no specific diagnosis listed (13% of total recorded immunoglobulin use). Clearly, this was less than optimal and caused concern among commissioners. In addition, this showed that improvements were required before the database was sufficiently robust to be able to link to payments by use. Further feedback from commissioners indicated widespread approval of the system used in Australia, with each indication for immunoglobulin carrying specific selection criteria for use, in particular, the need to use immunoglobulin as second- or third-line treatment in diseases for which there are a number of alternative treatment options. This approach, with selection criteria for each approved indication for immunoglobulin, has now been adopted in this guideline update. The need to employ selection criteria before prescribing will largely remove the need for panel decisions on prescribing, reducing the burden on IAPs and increasing focus on assessing patient outcome. Efficacy outcomes The database was not successful in the capture of data regarding the efficacy of immunoglobulin. Panels were encouraged to request up to three parameters by which efficacy could be determined in each patient [e.g., platelet count in patients with immune thrombocytopenic purpura (ITP)]. The purpose of this exercise was both to obtain preliminary data about efficacy in various conditions (fully accepting that lack of diagnostic criteria and other issues would make this a very crude analysis) and to provide feedback to individual Panels about the quality of their decision making. For example, if Panels repeatedly approved indications prioritised as Grey by the Demand Management Programme and the treatment was largely ineffective, review of these findings would improve IAP decision making. The decision has been taken to introduce efficacy outcomes for most indications. Monitoring of efficacy outcomes by commissioners may result in withholding payments to Trusts if efficacy outcomes have not been recorded in the database. Efficacy outcomes are expected to play an important role in the decision-making process of IAPs in cases in which continuation of immunoglobulin treatment is requested beyond the short- and long-term durations defined in the next section. 1 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Definitions of duration of immunoglobulin treatment The definitions of short-term and longterm treatment durations are refined in this update, with each approved indication for immunoglobulin now approved on the basis of short-term (3 months) and long-term (3 months) treatment needs. The definitions of duration of treatment are included in the table below. IAPs and commissioners together will make decisions on treatment extensions. short-term treatment Three prescribed doses of up to 2 g/kg, given at appropriate clinical intervals 3 months The treatment episode ends at 3 months. The National Immunoglobulin Database will record treatment re-initiation as a new treatment episode based on a new panel decision. It is expected that the IAP decision will be influenced by the outcome measures recorded on the database. 3 months Treatment reviews should be conducted annually. The National Immunoglobulin Database will record treatment re-initiation as a new treatment episode based on a new panel decision. It is expected that the IAP decision will be influenced by the outcome measures recorded on the database.* Long-term treatment *The primary immunodeficiencies are exempt from funding termination at 1 year. Recommended dosing of immunoglobulin The Second Edition of the Clinical Guidelines did not provide specific dosing recommendations; it is widely accepted that the standard immunomodulatory dose of 2 g/kg is usually divided into five daily infusions of 0.4 g/kg, although some physicians prefer to use two daily doses of 1 g/kg each. The database infusion records were incomplete and, therefore, it was not possible to fully interpret the data and decipher the dosing that had been used. This update to the guidelines now provides specific dosing recommendations for each of the conditions for which prescribing is regarded as appropriate. Immunoglobulin users are expected to record the dosing employed in the national database. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 An ongoing issue for diseases that require long-term immunoglobulin treatment is that once responsiveness to intravenous immunoglobulin (IVIg) is proven for a patient using standard immunomodulatory dosing, the `maintenance' dosing required to maintain the therapeutic response is not well characterised. In this update, the dosing recommendations for some neurological indications include `time to relapse' as the interval between doses. This approach is supported by recent evidence from The Oxford Programme for Immunomodulatory Immunoglobulin Therapy, which was set up to review multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) treatment with immunoglobulin. In view of the uncertainty of both remission and disease progression in CIDP and MMN, The Oxford Programme reviewed the dose and infusion frequency of patients on a regular basis and showed that increasing the infusion interval proved successful in some patients and resulted in treatment discontinuation [2]. The study also indicated that the precise dose and infusion interval to keep each patient asymptomatic was not predictable, but the authors suggested a rough guide: patients in whom responses last 20% more than IBW, prescribers should consider using adjusted-bodyweight dosing of immunoglobulin. Infusion rates for intravenous immunoglobulin Initial intravenous infusion rates are low, and if well tolerated, the rate of administration may be increased, as specified in the products' Summary of Product Characteristics (SPC). For certain products, the SPC indicates that if the higher rate is tolerated, the rate may be further increased in primary immunodeficiency (PID) patients to the maximum infusion rate. Higher infusion rates may lead to improved convenience for patients and may reduce nursing time and the need for hospital resources. Infusion rates for each of the licensed immunoglobulins are provided in the table below. Immunoglobulin should be administered according to the manufacturers' recommendations. The table below gives the infusion rates, and the infusion time at maximum infusion rate of 1 g/kg dose in a 70 kg person. Infusion rates Infusion time of 0 g in minutes at max. rate 100 250 500 640 125 200 125 241 83 Product Baxter Kiovig BPL Gammaplex BPL Vigam Biotest Intratect CsL Privigen Grifols flebogamma Grifols flebogamma 10 Octapharma Octagam Octapharma Octagam 10 Initial 0.5 mL/kg/h for 30 mins 0.01?0.02 mL/kg/min for 15 mins 0.01?0.02 mL/kg/min for 30 mins 1.4 mL/kg/h for 30 mins 0.3 mL/kg/h 0.01?0.02 mL/kg/min for 30 mins 0.01 mL/kg/min for 30 mins 1 mL/kg/h for 30 mins 0.01?0.02 ml/kg/min for 30 mins Maximum 6 mL/kg/h (8 ml/kg/h in PID) 0.04?0.08 mL/kg/min 0.04 mL/kg/min (max. 3mL/min) 1.9 mL/kg/h 4.8 mL/kg/h (7.2 mL/kg/h in PID) 0.1 mL/kg/min 0.08 mL/kg/min 5 mL/kg/h 0.12 ml/kg/min 1 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use subcutaneous administration Subcutaneous immunoglobulin (SCIg) as replacement therapy for primary immune deficiency disease and as immunomodulatory therapy for some autoimmune diseases, including peripheral neuropathies, can be a safe, effective, and convenient alternative to intravenous therapy. Subcutaneous administration can offer advantages that may be important for many patients [3]. Although SCIg is typically administered weekly by infusion pump, administration by a rapid push technique may provide a greater degree of convenience, and recent evidence suggests it is a safe and effective method. Seventy-four patients with primary immune deficiency disease received an average SCIg dose of 32 g/month split into an average of three times per week. Volume per site ranged from 3 to 20 mL, typically administered over 5?20 min. Mean serum IgG levels did not differ significantly compared with those receiving infusion and only two patients discontinued therapy because of an adverse event [4]. Recent evidence suggests that individualising the dosage based on measured serum IgG levels and the clinical response is preferable to using mean pharmacokinetic parameters [5]. Findings from the Oxford Self Infusion at Home Programme for CIDP and MMN also suggest that the dose of immunoglobulin and the serum IgG trough level are individual to each patient [2]. Recommendation Prescribers should consider the comparative advantages of intravenous and subcutaneous administration for individual patients requiring immunoglobulin treatment where this is clinically appropriate. Table. Subcutaneous immunoglobulin products licensed in the UK CSL Vivaglobin Baxter Subcuvia Octapharma Gammanorm BPL Subgam CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 RefeReNCes 1. NICE clinical guideline 98. Neonatal Jaundice. Nice, 2010. 2. Lucas M, Hugh-Jones K, Welby A, et al. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol 2010;30 Suppl 1:S84?9. 3. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112:1?7. 4. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis. J Clin Immunol 2010;30:301?7. 5. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin Immunol 2011;139:133?41. 1 sUMMARY TABLes PRIMARY AND seCONDARY ANTIBODY DefICIeNCY sTATes selection criteria A specific PID diagnosis must be established by a clinical immunologist Outcome measures are not required Condition s L Outcomes for review Dosing Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Primary immunodeficiencies (associated with significant antibody defects) Profound B cell depletion and/or significant antibody deficiency Outcome measures are not required Thymoma with immunodeficiency HSCT in primary immunodeficiencies PID patients undergoing HSCT Outcome measures are not required CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Specific antibody deficiency Approval by a clinical immunologist, AND Severe, persistent, opportunistic or recurrent bacterial infections despite continuous oral antibiotic therapy for 3 months, AND Documented failure of serum antibody response to unconjugated pneumococcal or other polysaccharide vaccine challenge Underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated; OR Hypogammaglobulinaemia associated with NHL, CLL, MM or other relevant B-cell malignancy confirmed by haematologist; AND ? Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 3 months ? IgG 1 dose required if thrombocytopenia persists Clinical suspicion in antenatal or neonatal setting based on clinical and laboratory features: Thrombocytopenia or spontaneous haemorrhage in the foetus; OR Thrombocytopenia with or without haemorrhage in the neonate; OR Unexplained foetal death in a previous pregnancy and the presence of maternal platelet-specific allo-antibodies that are known or suspected to cause this condition (most commonly HPA-1a or HPA-5b) Symptomatic or severe anaemia (Hb 15, acute rising Any significant clearance of C. diff. creatinine and/or signs/symptoms Duration of hospital in-patient stay of colitis) not responding to oral vancomycin 125 mg qds, highdosage oral vancomycin +/- iv metronidazole 500 mg tds is recommended; the addition of oral rifampicin (300 mg bd) or IVIg may be considered. If multiple recurrences, especially if evidence of malnutrition, wasting etc., consider IVIg Severe or recurrent Clostridium difficile colitis 0.4 g/kg, one dose, and consider repeating continued Other selection criteria Diagnosis of streptococcal or staphylococcal TSS, preferably with isolation of organism; AND Failure to achieve rapid improvement with antibiotic therapy and other supportive measures; AND Life-threatening Diagnosis by a dermatologist; AND Involved body surface area > 10%; AND When other treatments are contraindicated; OR The condition is life-threatening Resolution of the disease 2 g/kg, preferably as a single dose, or divided over 3 consecutive days Improvement of FBC, ALK, CPK Reduction in hospital inpatient stay Survival (yes/no) 2 g/kg as a single dose continued Outcomes for review Dosing Condition s L Staphylococcal or streptococcal toxic shock syndrome Toxic epidermal necrolysis, Stevens Johnson syndrome Transplantation (solid organ) AIT Up to 2 g/kg to be repeated as per DSA, in renal desensitisation at 0.1 g/kg for 8?12 doses AMR Up to 2 g/kg to be repeated for 2?3 doses Viral pneumonitis 0.5 g/kg for 5 days CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Antibody Incompatible Transplant AIT and AMR* (AIT) Renal Patients in whom renal, heart or Type of renal transplant lung transplant is prevented HLA class DSA because of antibodies Rejection episodes Patient survival Antibody Mediated Rejection Graft survival (AMR) Renal function = eGFR (MDRD) Patients experiencing steroid Cardiothoracic resistant rejection or where other DSA therapies are contraindicated after Patient survival renal, heart and/or lung transplant Length of ITU and hospital stay Graft function (heart = ejection Viral pneumonitis fraction; lung = spirometry) Patients experiencing viral pneumonitis following heart and/or Viral pneumonitis* lung transplant (viruses to include Cardiothoracic HSV, VZV, CMV, RSV, but excluding Virus type influenza virus) Reversal of radiological infiltrates Length of hospital stay Survival *These parameters will be reviewed after one year, at which time specific outcome criteria will be formulated. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use sUMMARY Of GReY INDICATIONs Grey indications are those diseases for which the evidence is weak, in many cases because the disease is rare. Approval from both the local IAP and the PCT is required for immunoglobulin treatment. In cases of `unlisted' diseases, those not listed in the guidelines are to be considered as Grey. Even if the disease is unlisted, the diagnosis and locally agreed efficacy criteria are to be recorded in the database. Immune-mediated disorders with limited evidence of immunoglobulin efficacy Acute disseminated encephalomyelitis (if high-dose steroids have failed) Autoimmune encephalitis (including NMDA and VGKC antibodies, among others) Catastrophic antiphospholipid syndrome Cerebral infarction with antiphospholipid antibodies Chronic ITP Complex regional pain syndrome CNS vasculitis Intractable childhood epilepsy Neuromyotonia Opsoclonus Myoclonus Post-exposure prophylaxis for viral or pathogenic infection if intramuscular injection is contraindicated, or treatment when hyperimmune immunoglobulins are unavailable Pyoderma gangrenosum Systemic juvenile idiopathic arthritis Systemic vasculitides and ANCA disorders Urticaria (severe, intractable) Presumed immune-mediated disorders with little or no evidence of efficacy Acquired red cell aplasia NOT due to parvovirus B19 Acute idiopathic dysautonomia Aplastic anaemia/pancytopenia Atopic dermatitis/eczema Autoimmune neutropenia Chronic facial pain Diabetic proximal neuropathy Haemolytic uraemic syndrome PANDAS Paraneoplastic disorders that are known not to be B- or T-cell mediated POEMS SLE without secondary immunocytopenias (including juvenile) CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Removed from Grey: ? Secondary antibody deficiencies INDICATIONs fOR WHICH IVIG Is NOT ReCOMMeNDeD (now Blue) ? Acquired vWd (now Blue) ? Post-transfusion hyperhaemolysis (now with haemolytic anaemia) ? Graft versus host disease (delete) ? SLE with secondary immunocytopenias (included in the relevant cytopenias) ? Infection following BMT or HSCT (included in Blue) ? Polymyositis (now Blue) ? Transplantation indications (now Blue) ? Immunodeficiency secondary to paediatric HIV infection ? Autologous BMT ? Adrenoleukodystrophy ? Alzheimer's disease ? Amyotrophic lateral sclerosis ? Chronic fatigue syndrome ? Critical illness neuropathy ? Multiple sclerosis ? Rheumatoid arthritis ? Neonatal sepsis (prevention or treatment) ? Sepsis in the intensive care unit not related to specific toxins or C. difficile ? Asthma ? Graves' ophthalmopathy ? IVF failure ? Recurrent spontaneous pregnancy loss CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Next section contains the replacement pages of second edition CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Update for pages 28?30 IMMUNOLOGY Primary immunodeficiency disorders (associated with significant antibody defects) Antibody deficiencies may arise as primary disorders with a known or suspected genetic basis or secondary to a variety of other diseases, drugs and environmental or iatrogenic factors. They may occur in isolation or in association with defects in other effector components of the immune system (combined defects). Significant primary antibody deficiencies collectively account for the majority of primary immunodeficiency syndromes encountered in clinical practice [1,2]. The hallmark clinical presentation is recurrent or persistent bacterial infection, but these disorders are also associated with a heterogeneous variety of other infectious and non-infectious complications and with a high incidence of chronic, structural tissue damage, particularly in the respiratory tract. Clinical recognition of primary antibody deficiency is frequently delayed with consequent acute and chronic ill health, diminished Common Common variable immunodeficiency group (CVID) X-linked agammaglobulinaemia quality of life, and decreased life expectancy. Primary antibody deficiency can present at any age. Taken together, the primary antibody deficiency disorders account for at least half of all primary immunodeficiency syndromes. For some conditions, internationally-agreed diagnostic criteria have been established [3], but in other disorders formal case-definition criteria are lacking. The evidence base for current practice in the recognition, diagnosis and management of antibody deficiency has recently been reviewed [4]. Disorders which generally require immunoglobulin replacement as a central component of their management are presented below. Diagnosis, particularly of primary deficiencies, is frequently delayed or overlooked [1,5]. Many patients present with established structural tissue damage, especially in the lungs, which is essentially irreversible even with optimal treatment. Diagnostic aims are to a) identify, or exclude, significant antibody deficiency, b) differentiate primary from secondary disease and c) delineate, where possible, a precise diagnosis. Less common Germinal centre class switch recombination defects (`Hyper-IgM syndromes') Other primary antibody deficiency (XLA) (including unclassifiable disorders) Combined immunodeficiencies (including severe combined immunodeficiency (SCID) and unclassifiable disorders) 0 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use The goals of management are to prevent complications or retard their progression, optimise quality of life, working capacity and life expectancy and, in children, ensure optimal growth and development [6]. Replacement therapy with polyclonal human normal immunoglobulin is the cornerstone of management for significant primary antibody deficiency disorders. No viable alternatives exist to this essential, basic component of treatment, particularly in the context of severe, persistent or recurrent bacterial infections. For most patients, replacement therapy is a lifelong requirement. Existing formulations replace deficient IgG only and are given by either intravenous or subcutaneous infusion in a hospital setting or, increasingly, within domestically-based programmes. Subcutaneous and intravenous preparations are therapeutically equivalent [7]. All preparations carry risks of adverse, infusion-related reactions and both real (hepatitis C) and theoretical (vCJD) risks of transmissible disease. Replacement therapy increases life expectancy and reduces the frequency and severity of infections, antibiotic usage and hospital admissions [4]; however, patients remain susceptible to sporadic breakthrough infections [8]. Optimal dosing and target levels for IgG are not known but higher doses are more effective than low-dose regimens in reducing infection rates and risk of chronic tissue damage. However, even apparently adequate treatment may fail to completely retard progression of established disease complications such as bronchiectasis [9]. Replacement therapy is frequently targeted at achieving a sustained or pre-infusion trough serum IgG level within the normal range (6?16 g/L). There is evidence that improved outcomes, particularly in respect of respiratory infection, are associated with higher serum IgG levels up to at least 10 g/L [10]. Dosage should generally be initiated at 0.4?0.6 g/kg/month, but individual patients may require higher doses in the long term. The goal of therapy in individual cases should be to improve clinical outcome rather than achieve a minimum target level of serum IgG [11]. Dose requirements are commonly increased in the context of secondary structural tissue damage (especially in the respiratory tract) or co-existent chronic inflammatory conditions. Risk assessments for ongoing therapy with immunoglobulin should be carried out regularly (including the need to continue with active treatment). Recommendation Replacement immunoglobulin therapy in patients with significant, symptomatic primary defects of antibody production or function should be tailored to individual patient outcomes with the minimum aim of maintaining serum IgG levels within the age-related normal range (grade B recommendation, level IIb evidence). CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 Other specific Disorders Thymoma with immunodeficiency (Good's Syndrome) Good's syndrome is a complex CVID-like condition where thymoma is found in association with profound B cell lymphopenia and quantitative or functional antibody deficiency. Infection frequencies correlate better with numerical B-cell depletion than with hypogammaglobulinemia. Thymectomy rarely results in normalisation of immunoglobulin levels and the syndrome may therefore constitute, and be classified as, a primary rather than secondary defect and, in respect of any antibody deficiency, be treated as for other primary antibody defects [2,12]. diagnosis is established. Pre-existing infection in the high-risk situation of a combined primary immunodeficiency reduces the chances of a successful outcome from a haemopoietic stem cell transplant. Treatment with immunoglobulin should be continued following transplantation until reconstitution of B cells and antibody production has been achieved. In some cases, prolonged immunoglobulin replacement therapy is required. Recommendation Immunoglobulin replacement therapy should be considered an important adjunct to haemopoietic stem cell transplantation in the management of some primary immunodeficiency disorders. Duration of treatment should be based on individual reconstitution of B-cell function post-transplantation (grade C recommendation, level III evidence). Recommendation Immunoglobulin replacement is recommended for patients with thymoma associated with profound B-cell depletion and/or significant antibody deficiency (grade C recommendation, level III evidence). specific antibody deficiency Specific antibody deficiency is characterised by an inability to mount adequate humoral responses to polysaccharide antigens, with otherwise normal immunoglobulins [13]. Robust case definition is currently hampered by a lack of consensus on in-vitro diagnostic criteria. Consequently, uniform recommendations for treatment are yet to be developed. Most cases appear to have a relatively mild clinical phenotype (encompassing mainly respiratory infections) which Combined immunodeficiencies requiring haemopoietic stem cell transplantation In this group of disorders, including Severe Combined Immunodeficiency and occurring predominantly in children, immunoglobulin therapy is required as a central measure to protect against infection and should be implemented as soon as possible after the CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use can be managed with prophylactic antibiotics and acute treatment of breakthrough infections. Immunoglobulin replacement is reserved for those cases where prophylactic antibiotics fail to control either the frequency or severity of breakthrough infections. Recommendation Immunoglobulin replacement therapy may be required in a proportion of infants with prolonged physiological delay of native immunoglobulin production. Where required, the planned duration of therapy should be defined prior to initiation of active treatment (grade C recommendation, level III evidence). Recommendation Immunoglobulin replacement therapy is recommended in specific antibody deficiency in cases of failure of prophylactic antibiotic treatment where severe, persistent, opportunistic or recurrent breakthrough infections are encountered (grade C recommendation, level III evidence). secondary antibody deficiency Secondary antibody defects are found in a wide range of circumstances (in association with drugs, malignant disease, chronic infections, protein-losing states, systemic inflammatory diseases, trauma and iatrogenic factors such as splenectomy). Infections associated with low measured antibody levels appear to be relatively uncommon in secondary deficiencies, with the exceptions of hypogammaglobulinaemia linked with haematological malignant disease, occasional cases of drug-associated deficiency and rare cases of nephrotic syndrome [15]. Dosage and treatment duration are important factors in drug-associated deficiencies. The deficit may, or may not, be reversible on cessation of therapy. The selection criteria for IVIg to treat hypogammaglobulinaemia linked with haematological malignancy includes the requirement to document failure of serum antibody response to Transient hypogammaglobulinaemia of infancy Hypogammaglobulinaemia in young children is often transient, reflecting delayed maturation of the immune system. In the majority of such children, immunoglobulin levels normalise by the age of around 4 years, but in a minority this can be delayed until 11 or 12 years of age. Most of these children are affected by frequent, minor infections, which can be managed with early, acute antibiotic usage or antibiotic prophylaxis [14]. However, in a small minority, infections are more severe and cannot be controlled or prevented with antibiotics alone. In such circumstances, immunoglobulin replacement is required until normalisation of endogenous antibody production. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use unconjugated pneumococcal or other polysaccharide vaccine challenge. Although this may sound onerous from a practical point of view, the intention is simply to ensure that a patient's response to polysaccharide vaccination is included as a component of the evaluation for IVIg therapy. For example, if a patient received pneumococcal polysaccharide vaccine 3 months previously and their specific antibody levels are low, it would seem reasonable to prescribe immunoglobulin. However, if the patient was vaccinated many years previously, it would be reasonable to vaccinate again and assess the functional antibody response before immunoglobulin was prescribed. Recommendation Immunoglobulin replacement therapy is recommended in secondary antibody deficiency if the underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated, or is associated with B-cell malignancy where severe infections with encapsulated bacteria are persistent despite prophylactic antibiotic therapy (grade C recommendation, level III evidence). RefeReNCes 1. Eadles-Perner A-M, Gathmann B, Knerr V, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06. Clin Exp Immunol 2007;177:306?12. 2. Geha RS, Notarangelo LD, Casanova JL, et al. for the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776?94. 3. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Clin Immunol 1999;93:190?7. 4. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol 2007;149:410?23. 5. Seymour B, Miles J, Haeney MR. Primary antibody deficiency and diagnostic delay. J Clin Pathol 2005;58:546?7. 6. Folds JD, Schmitz JL. Clinical and laboratory assessment of immunity. J Allergy Clin Immunol 2003;111(Suppl. 2):S702?11. 7. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin therapy. J Clin Immunol 2000;20:94?100. 8. Pettit SJ, Bourne H, Spickett GP. Survey of infection in patients receiving antibody replacement treatment for immune deficiency. J Clin Pathol 2002;55:577?80. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 9. Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allerg
Url: /Media/SUHTExtranet/TrustMedicinesFormulary/Forms/DH-IVIg-approved-indications-Full-Guidance-July-2011.pdf

UHS adult major trauma guidelines

Description: Adult Major Trauma Guidelines University Hospital Southampton NHS Foundation Trust Dr Mark Baxter Director of Major Trauma, Consultant in Older Persons Medicine Prof Rob Crouch Deputy Director of Major Trauma, Consultant Nurse in Emergency Medicine Emma Bowyer Major Trauma Centre and Wessex Trauma Network Manager Amendment’s log No. Amendments 1. Update Wessex Trauma Network Automatic acceptance tool 2. Hyperlinks added from contents page Page No. 22 4 3. Updated Guideline on the management of chest 107 injuries and chest decompression 4. Burns Operational Guidance added 55 5. Adult Major Trauma: Prophylactic Antibiotics guideline 81 Flowchart added to section 3 6. Adult Major Trauma; Prophylactic Antibiotic guideline 124 added to section 4 Date Sept 2021 Oct 2021 (v7.1) Apr 2022 (v7.2) Apr 2022 (v7.2) May 2022 (v7.3) May 2022 (v7.3) 2 NOTE: These guidelines are regularly updated. Check the intranet for the latest version. DO NOT PRINT HARD COPIES Please note these Major Trauma Guidelines are for UHS Adult Major Trauma Patients. The Wessex Children’s Major Trauma Guidelines may be found at http://staffnet/TrustDocsMedia/DocsForAllStaff/Clinical/WessexChildre nsMajorTraumaGuideline/WessexChildrensMajorTraumaGuidelines.pdf NOTE: If you are concerned about a patient under the age of 16 please contact SORT (02380 775502) who will give valuable clinical advice and assistance by phone to the Trauma Unit and coordinate any transfer required. http://www.sort.nhs.uk/home.aspx Please note current versions of individual University Hospital Southampton Major Trauma guidelines can be found by following the link below. http://staffnet/TrustDocuments/Departmentanddivisionspecificdocuments/Major-trauma-centre/Major-trauma-centre.aspx 3 Table of Contents (Hyperlinked) 1 SECTION 1: PREPARATION FOR MAJOR TRAUMA ADMISSIONS ................................................................................ 7 1.1 PRE-HOSPITAL TRIAGE & TRAUMA UNIT BYPASS TOOL ............................................................................................................ 7 1.2 ATMIST....................................................................................................................................................................... 10 1.3 ADULT MAJOR TRAUMA TEAM ACTIVATION ........................................................................................................................ 11 1.4 ADULT MAJOR TRAUMA TEAM COMPOSITION ..................................................................................................................... 12 1.5 RESPONSIBILITIES & ROLES OF TRAUMA TEAM MEMBERS ...................................................................................................... 13 1.6 HANDS-OFF HANDOVER................................................................................................................................................... 19 1.7 TRAUMA TEAM LEADER: EXECUTIVE ROLE ........................................................................................................................... 20 1.8 SITE MANAGER .............................................................................................................................................................. 21 1.9 SECONDARY TRAUMA TRANSFERS ...................................................................................................................................... 22 2 SECTION 2: TRAUMA RESUSCITATION ( ABCDE) ................................................................................................. 25 2.1 CATASTROPHIC HAEMORRHAGE......................................................................................................................................... 25 2.2 AIRWAY ........................................................................................................................................................................ 35 2.3 BREATHING ................................................................................................................................................................... 38 2.4 CIRCULATION ................................................................................................................................................................. 41 2.5 DISABILITY..................................................................................................................................................................... 46 2.6 EXPOSURE & ENVIRONMENT ............................................................................................................................................ 54 2.7 TRAUMA IMAGING.......................................................................................................................................................... 55 2.8 BURNS – OPERATIONAL GUIDANCE .................................................................................................................................... 56 2.9 ADMISSION DESTINATION ................................................................................................................................................ 57 3 TRAUMA RESUSCITATION SUPPORTING DOCUMENTS............................................................................................ 58 3.1 APPLICATION OF CELOXTM GAUZE .................................................................................................................................... 58 3.2 BELMONT RAPID INFUSER ................................................................................................................................................ 59 3.3 RESUSCITATIVE THORACOTOMY......................................................................................................................................... 60 3.4 MAJOR TRAUMA AIRWAY ALGORITHM ............................................................................................................................... 63 3.5 FRONT OF NECK ACCESS PROCEDURE ................................................................................................................................. 65 3.6 PRE-RSI CHECKLIST......................................................................................................................................................... 66 3.7 IMMEDIATE RSI CHECKLIST............................................................................................................................................... 67 3.8 TRAUMA BAY CHECKLIST.................................................................................................................................................. 68 3.9 RSI PACK LIST ................................................................................................................................................................ 71 3.10 RIB FRACTURE PATHWAY ................................................................................................................................................. 73 3.11 SCOOP STRETCHERS ........................................................................................................................................................ 77 3.12 MAJOR TRAUMA CT HOT REPORT ..................................................................................................................................... 79 3.13 ADULT MAJOR TRAUMA: PROPHYLACTIC ANTIBIOTICS GUIDELINE - FLOWCHART ......................................................................... 81 4 STANDARD OPERATING PROCEDURES .................................................................................................................... 83 4.1 UHS MANAGEMENT OF EXTREMITY BLEEDING & TOURNIQUET SOP........................................................................................ 83 4.2 UHS MAJOR HAEMORRHAGE PROTOCOL............................................................................................................................ 92 4.3 UHS GUIDELINE FOR THE MANAGEMENT OF CHEST INJURIES AND CHEST DECOMPRESSION IN ADULT MAJOR TRAUMA ................... 107 4.3.1 Executive Summary ........................................................................................................................................ 107 4.3.2 Introduction.................................................................................................................................................... 108 4.3.3 Scope .............................................................................................................................................................. 108 4.3.4 Aim/purpose................................................................................................................................................... 108 4.3.5 Definitions ...................................................................................................................................................... 109 4.3.6 Guideline for the management chest injuries and chest decompression in Adult Major Trauma ................. 109 4.3.7 Implementation.............................................................................................................................................. 112 4.3.8 Roles and responsibilities ............................................................................................................................... 112 4.3.9 Document review ........................................................................................................................................... 112 4.3.10 Process for monitoring compliance ........................................................................................................... 112 4.3.11 Appendices ................................................................................................................................................ 113 4.3.12 References ................................................................................................................................................. 113 4.4 UHS MAJOR TRAUMA TEAM SOP................................................................................................................................... 114 4.5 ADULT MAJOR TRAUMA: PROPHYLACTIC ANTIBIOTIC GUIDELINE............................................................................................ 124 4.5.1 Version control ............................................................................................................................................... 124 4 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 4.5.7 4.5.8 4.5.9 4.5.10 4.5.11 4.5.12 4.5.13 Index............................................................................................................................................................... 125 Introduction.................................................................................................................................................... 126 Scope .............................................................................................................................................................. 126 Aim/purpose................................................................................................................................................... 126 Definitions (if necessary) ................................................................................................................................ 126 Adult Major Trauma Antibiotic Flowchart ..................................................................................................... 127 Implementation.............................................................................................................................................. 128 Roles and responsibilities ............................................................................................................................... 128 Document review....................................................................................................................................... 128 Process for monitoring compliance ........................................................................................................... 129 Appendices ................................................................................................................................................ 129 References ................................................................................................................................................. 129 5 Introduction ‘These guidelines are the current policies and practice for the management of adult major trauma patients at University Hospital Southampton. They have been designed to provide a day to day framework for the management of patients; including the roles and responsibilities of clinical teams and their members. The guidelines were produced to try and ensure timely, consistent, high-quality care for all patients whatever day or time of day they present, recognising that these are challenging and often stressful cases. There will be situations when it is appropriate to deviate from the guidelines or where the guidelines do not cover the specific circumstances. In these cases it is essential that care of the patient is the foremost consideration, that senior staff are directly involved and that documentation is clear. If in doubt, seek senior advice and document their involvement. This second edition of the guidelines reflects the changes in practice in major trauma over the last 6 years together with changing national guidance and policy. My personal thanks to all members of the clinical and support teams who have contributed to the development of excellent practice at UHS and who have contributed to this revision. Thanks in particular to Dr Liz Shewry and Dr Simon Hughes, who begun these revisions and to Major Alan Weir who continued with this unenviable task. In addition, this second edition would not be possible without such a comprehensive first edition. Thanks for the first edition go to Dr Andy Eynon, Dr Liz Shewry and Dr Simon Hughes, who authored the first edition of these guidelines in 2012. The first edition has guided Major Trauma Care across Wessex and further afield for nearly a decade.’ Dr. Mark Baxter Director of Major Trauma, University Hospital Southampton, 6 1 Section 1: Preparation for Major Trauma Admissions 1.1 Pre-hospital Triage & Trauma Unit Bypass Tool The pre-hospital triage & trauma unit bypass tool was developed by the Wessex Trauma Network (WTN) to identify patients who have or are at high risk of having sustained major trauma. Patients who are within a 60 minute travel time of UHS may be transferred direct to UHS as the Major Trauma Centre (MTC), bypassing hospitals closer to the scene of the accident. The rationale for this is that it is time to definitive treatment rather than time to arrival in hospital that makes the biggest difference in outcomes. UHS was chosen as the MTC as it has all major trauma services on site. The pre-hospital team (Ambulance Service, BASICS, HIOWAA) will alert the ED that a patient with major trauma is en route. It is expected that a basic ATMIST (see p9) handover will be received with details of the mode and likely time of arrival of the patient. Patients who are outside a 60 minute travel time or who are deemed to be at risk of imminent airway compromise or have catastrophic haemorrhage will go initially to their nearest trauma unit (TU) for resuscitation. Once resuscitated, if the TU feel that the patient’s injuries are beyond their local facilities, the patient will be transferred on to either the MTC or another TU with specialist facilities (see Section 1.09 Secondary Trauma Transfers, p22). Certain hospitals have been designated as local receiving hospitals (LRH) by the Wessex Trauma Network. Trauma patients will only go to these hospitals if there is an imminent cardiac arrest or immediate airway problem. Patients will be expected to have only these immediate life-threatening conditions controlled before onward transfer to a TU or MTC. 7 8 Figure 1. Trauma Triage Tool (2021) 9 1.2 ATMIST Ambulance services, including the air ambulance service, are using the ATMIST handover tool. This gives basic information to enable preparations to be made to receive the patients. The sticker below is completed by the team leader and then it is stuck into the trauma booklet on arrival in ED resus. Figure 2. Pre-hospital alert ATMIST sheet 10 1.3 Adult Major Trauma Team Activation A two-tier response to trauma has been developed at UHS. A full trauma team response (Level 1 trauma call) should be instigated by the ED Consultant where a patient triggers a pre-hospital major trauma call and there is concern by the ED team that a full trauma team response is required. For less severe trauma it may be appropriate to activate the ED trauma team alone (Level 2 trauma call), which can be escalated if more significant injury is found. Criteria for activating a Level 1 trauma call (Figure 3) are based on physiology, anatomical injury, and mechanism of injury, however, this is not an exhaustive list and full trauma team activation is at the discretion of the receiving clinicians. To activate a Level 1 trauma call, contact Switchboard on 2222 and request “Adult Trauma Team, ED Resus” Physiological Respiratory rate 29 Or Pre hospital Sp02 o 110 GCS Motor Score of 4 or less Or Pre- hospital GCS of 1 fractured long bone Suspected major pelvic injury Trauma Triage Tool Activation (Trauma Unit Bypass) Other Considerations Pre-hospital intubation (Mandates Level 1 Call) Senior Clinician Concern (including mechanism) Gunshot wounds, stabbing, impaling Falls > 6 metres High impact RTC (Ejection, death of vehicle occupant, pedestrian struck by vehicle > 30mph) For the ≥ 65 age group consider • Systolic BP of ≤ 110 mmgHg • Heart Rate of ≥ 100 bpm • Fall with GCS of ≤ 12 • Taking Anticoagulants • Co-morbidities; Liver disease, renal failure, heart failure, COPD Figure 3. Criteria for Level 1 Trauma Response (December 2020) 11 1.4 Adult Major Trauma Team Composition Level 2 Trauma Team ED Consultant or ED ST4+ ED Doctor/ACP ED Nurse in charge ED Nurse x 2 HCA Level 1 Trauma Team Level 2 Trauma Team Members plus: ED Consultant Trauma Orthopaedic Consultant Major Trauma Anaesthetist Named Anaesthetist (Day) GICU SpR ODP / tech General Surgery SpR / Cons Orthopaedic Surgery SpR Site manager (if helipad arrival) Radiographer Major Trauma Clinical Coordinator (Daytime) bleep 1780 (Daytime) bleep 1783 bleep 1646 bleep 2110 bleep 1784 bleep 9990 bleep 2702 bleep 2238 bleep 1781 bleep 1963 There is agreement that the Neurosurgical SpR (bleep 2877) and Cardiothoracic SpR (bleep 9211) will not be part of unselected Level 1 calls. They may be contacted at the discretion of the Trauma Team if the pre-alert suggests their presence may be of benefit. Other specialists (eg ENT and MaxFax) may be contacted in a similar fashion. 12 1.5 Responsibilities & Roles of Trauma Team Members On receiving a major trauma alert, all members of the major trauma team should assemble in the ED Resus area to be briefed on the nature of the patient expected. This information should be written on a board or flipchart for the team to view throughout the trauma call. The Trauma Team Leader (TTL) will lead a team briefing and allocate roles in advance of the patient’s arrival. If a member of the team cannot attend within the given timeframe they should notify the ED immediately (x3807). If a specialty SpR cannot attend, the duty specialty Consultant must be informed and attend. CT CT should be informed that a potential major trauma patient will be arriving so that the scanner can be cleared and be on stand-by to perform a trauma series CT. The default emergency CT is the C level scanner adjacent to the ED (x6108 / x4999). Transfer equipment should be made ready in the expectation that the patient will be moving from resus to CT. Trauma mattresses are NOT to be used for Level 1 trauma cases. They should managed in the initial resuscitation phase on scoop, and transferred to CT/ Theatre / ITU on this scoop. If the patient remains in ED for a period of time following resuscitation then they may be transferred to a trauma mattress at this point. There is an agreed protocol for requesting a trauma series CT +/- limb angiography. The request is made electronically and then a single telephone call is made to the CT Radiographer to inform them of the request. The CT Radiographer will then inform the duty Radiology SpR who will approve request and provide the Hot Report to the trauma team. Major Haemorrhage (Code Red) If the pre-hospital information suggests that the patient has severe, life-threatening haemorrhage a ‘CODE RED’ should be called. This facilitates prompt requests for blood products from Blood Bank and allows the major trauma team to make adequate preparations for management e.g. preparation of tourniquet, preparation of rapid infuser. There is an allocated ‘Code Red Nurse’ for every shift. They should be identified when the trauma team assembles and if required prime the rapid infuser. A team of two is required for effective major haemorrhage management – a transfusion assist will be allocated to work with the ‘Code Red Nurse’ from the ED team. Consider allocation of ‘T’ (Transfusion) number for patients who have Code Red declared prehospital. A number of patient note folders and ‘T’ numbers have been pre-assigned. Blood Bank must be informed if a ‘T’ number is used, and they can issue FFP using a ‘T’ number. If a 13 ‘T’ number has already been allocated by HIOWAA then this must continue to be used on arrival at UHS. Most of the Air Ambulances carry blood for prehospital use. If HIOWAA has given blood please inform blood bank before their arrival as the Air Ambulance will need restocking. Helicopter Transfers If the patient is being transferred by helicopter, switchboard will be informed and asked to alert the helipad team (Site Manager, Portering staff). The Trauma Team is far more effective looking after major trauma patients in ED Resus rather than on the Helipad. Therefore, the priority is to transfer the patient from the Helipad to Resus before Hospital resuscitation commences. NOTE: Aside from the helipad team, no members of UHS staff are to attend the helipad even if the patient is critical 14 Trauma Team Roles Trauma Team Leader • Controls and manages the trauma team resuscitation • Makes decisions in conjunction with specialists • Priorities investigations and treatments • Is responsible for the handover and transfer • Undertakes the trauma transfer checklist, prior to departure from ED Before patient arrival • Ensures trauma team activated (consider additional specialties andseniority) • Liaises with Scribe • Ensures team members are booked in with Scribe • Introductions and roles assigned • Activates Code Red (if required). Consider plain film (CXR/PXR) if toounstable for CT • Ensures tranexamic acid is available • Briefs team. Rehearse emergency plan • Ensures Airway Assistant has started clock on patient arrival NOTE: It is imperative that the Trauma Team Leader maintains control and insists on MINIMUM noise from the Trauma Team members NOTE: The Team Leader will read aloud the Checklist for actions prior to leaving ED – the main indication for this is transfer to the CT Scanner. 15 Anaesthetist • Ensures equipment and anaesthetic drugs (Blue/Red CD pack and yellow fridge Pack) are available on patients arrival • Verbalises airway and anaesthetic plan to team leader and airway assistant • Communicates airway patency and issues to team leader and scribe on arrival • Communicates with team leader airway decision making following assessment. Ensure cervical spine immobilisation • Assess pupil size and reactivity • If indicated, RSI and ongoing sedation and ventilation • Provide ongoing assessment of GCS. Reassures patient on arrival, takes AMPLE history: A- Allergies M- Medications P- Past medical history L- Last meal E- Everything else relevant • Ensures neuro protective measures are undertaken for significant head injuries (30 degree trolley tilt, sedation, muscle relaxation, avoid tube ties and tight cspinecollar, avoid hypercapnia) • Arterial lines are rarely indicated. To avoid delay to CT this can usually be done after CT or in the operating theatre • Ensures theatres are informed as appropriate (bleep 2894 or named consultanton 1646) • Ensures CD book is signed NOTE: Insertion of invasive lines should not delay transfer to CT or theatre Airway Assistant • Completes airway check list prior to patients arrival and that difficultairway trolley is accessible if required (ask if c-mac is required) • Ensures Blue/ Red CD pack and yellow fridge pack are readily available with appropriate anaesthetic drugs drawn up in conjunctionwith Anaesthetist • Confirm airway plan • Start the clock on patient arrival • May assist with removing patients clothing, have scissors to hand • Assists anaesthetist in all airway interventions • Ensure time of intubation is recorded by scribe • Takes emergency airway equipment / drugs on any transfer(CT, Theatre, ICU) • Assists in the preparation patient for transfer to CT/theatres ASAP • Ensures CD book is signed 16 Primary Survey • Undertakes primary survey ABCDE. Clearly states findingsto Team leader and scribe • Performs procedures depending on skill levels and training. Confirmsskill level with team leader prior to patient arrival • If thoracostomies are present, re-finger to ensure patency.Is lung up or down? Delegate opposite side, if necessary • FAST scan if accredited and does not delay CT • Neurological exam needed before paralysing anaesthetic agent given • Ensure patient is kept warm • Ensures CT notified. Where indicated convey urgency of completingthe CT. Order any other radiology in discussion with the team leader,should this be appropriate Circulation • Ensures patient has two patent peripheral lines in situ (IV/IO • Ensures bloods are taken: FBC U&E LFT Crossmatch Coagulation Screen Venous Gases • Requests bloods and ensures these are sent to the lab • Performs procedures depending on skill levels and training. Confirms skill level with team leader prior to patient arrival • Administer drugs in conjunction with Drugs role • Undertakes secondary survey • Ensure patient is kept warm Monitoring/Packaging • Prepares for trauma call with warming devices • Removes all patient clothes including underwear and stored securely • Checks that all monitoring equipment is available • Connects patient monitoring on arrival • Ensures Bair Hugger / blankets are covering patient at all time • Ensures temperature is taken • Prepares patient for transfer to CT/theatres ASAP • Checks transfer stack as per the checklist • Helps with any procedures as identified e.g. catheter, chest drainand ART line 17 Drugs • Manages any external major haemorrhage if present on arrival • Assists Monitoring/Packaging with clothes removal • Liaise with Airway specialist and airway assistant to support a promptanaesthetic if required • Draws up drugs and administers them as prescribed • Helps with getting IV/IO access in conjunction with Circulation • Helps with any procedures as identified e.g. catheter, chest drainand ART line • Assists Monitoring/Packaging to prepare for transfer Scribe • Ensures correct PPE and identification worn • Use ED documentation • Records names, grades and specialities of all clinical staff attending plus time of arrival • Ensures clock is started when patient arrives • Records primary survey findings • Records all observations (including time of intubation). • Records all findings and interventions • Ensures wrist bands are applied including allergy • Observe for abnormal observation and signs indicatingpotential reactions to blood products Relative Liaison • Identify any relatives on their arrival to the department and take tothe relatives room • Ensure that relatives are kept up to date with information,where possible • To assist medical team in the delivery of patient updates and to stay with the family for further questions • If CPR is in progress discuss with team leader regarding witnessedresuscitation and if suitable offer to the relatives • Where appropriate accompany the relatives/important others to the area where the patient is to be care for next (or make sure theyare escorted) • If relatives/important others are not present whilst the patient is in theED resus room – ensure that a named individual is responsible for greeting them and passing on the necessary information 18 Code Red Prior to Arrival • Inform transfusion of code red being called and ask for MajorHaemorrhage Pack 1 • Ensure you are wearing the correct PPE and designated label • Remove x2 units of Emergency blood and scan into BloodTrak On Patient Arrival • Ensure blood products have been prescribed on the transfusion chart • Contact transfusion if major haemorrhage pack 2 is required andinform them of the requirements • Ensure the transfusion are aware of the patients destination andwhere further blood products are required to be sent Code Red Infuser Prior to Arrival • Ensure you are wearing the correct PPE and designated label • If appropriate prime the Belmont ready to infuse • Ensure Tranexamic acid 1g is available and consider second dose in massive haemorrhage On Patient Arrival • Administer blood products, under the direction of the team leaderas per the trust policy • Inform team leader when boluses have been delivered • Monitors compliance with 1:1 transfusion ratio (RBC:FFP) • Ensure the scribe has documented the number of boluses administered Code Red HCA Prior to Arrival • Ensure you are wearing the correct PPE and designated label On Patient Arrival • Takes crossmatch blood sample directly to the lab & waits for the Major haemorrhage pack 1 and bring back to ED resuscitation room • Brings blood products to ED resuscitation room and scans unitson arrival 1.6 Hands-off Handover Generally unless CPR is in progress, or there is airway compromise or concern over catastrophic haemorrhage, an ATMIST handover will be given by the ambulance staff whilst UHS staff stand-off the patient. The trauma team leader will first ask where the pre-hospital team are happy to give a 'hands off handover'. Ambulance staff assisted by UHS staff will transfer the patient from the stretcher to the trolley in resus. Patients should remain on the scoop-stretcher. 19 The ATMIST handover should be completed within 30 seconds and is designed to give ALL members of the trauma team the information necessary to proceed with the immediate care of the patient. Further information regarding the patient can be relayed to the Trauma team leader following the ATMIST handover. 1.7 Trauma Team Leader: Executive Role The ED Consultant has authority from the Chief Executive and Medical Director to request any specialty Consultant to attend. All UHS Consultants have a statutory duty to be able to respond in an emergency within 30 minutes of request. The Trauma Team Leader will: • Determine and arrange the appropriate destination for the patient i.e. theatre, ICU, ward • Ensure that medical staff of the appropriate seniority are involved in the care of the patient • Ensure that only essential imaging is performed • Ensure that necessary documentation has been completed a. Major trauma activation b. Trauma team attendance (including time of arrival and grade of doctor) c. The extent of examination performed in the ED and whether a further secondary examination is required d. The secondary survey must be signed off as complete at the earliest opportunity. The team leader is responsible for ensuring the survey is performed and documented. The default specialty to complete the secondary survey is the T&O Doctor e. Ensure spinal precautions are applied throughout where indicated f. Ensure that handover of a multi-trauma patient to a specialty service is formally documented. Until this has occurred, the patient will remain under the care of the Trauma Team Leader g. Handover between the Trauma Team Leader and the receiving team Doctor should always be done in person with a written handover of all admissions and any necessary actions NOTE: The MTC Consultant or Trauma Team Leader must always attend the CT scanner and liaise with the Anaesthetist as to the patient’s injuries and planned destination after CT. In exceptional circumstances the TTL can delegate escorting the patient to CT to an appropriately senior Doctor from outside ED – e.g. the T&O Consultant. Their principal role is not to guide resuscitation (typically this will be performed by the anaesthetist) but to ensure prompt liaison with other teams (e.g. Neurosurgery) as required. 20 1.8 Site Manager It is essential that patients can move as swiftly as possible from the ED to their place of definitive care. Patients may require immediate theatre / ICU bed / ward bed. Patients requiring immediate theatre: • Coordination of theatre will be done by the TTL with the Named Anaesthetic Consultant • Patients with isolated head / spinal cord injury requiring immediate theatre should be managed in the appropriate specialist theatre • The duty Anaesthetic Consultant will be responsible for coordinating the ongoing resuscitation NOTE: F Level Theatres recovery can be used for patients requiring ongoing resuscitation after CT whilst theatre is being prepared. Patient requiring ICU bed In principle, patients with a primary neurological diagnosis (head or spinal cord injury) should be managed on Neuro ICU with the proviso that there are very limited resuscitation facilities available in the Wessex Neurological Centre. As such, patients with ongoing resuscitation needs or with significant cardiovascular injury are best managed initially on General ICU. Patient requiring Ward bed Patients with single system injury are best managed on wards with experience of managing that injury. Patients with multi-system injury requiring a ward bed should by default go to the Major Trauma Ward (F1). Patients with isolated thoracic injuries will be admitted to the thoracic ward under the care of Thoracic surgery. NOTE: The Trauma & Orthopaedics Consultant is responsible for polytrauma patients where there is no clear single specialty. 21 1.9 Secondary Trauma Transfers The secondary transfer tool has been developed by the Wessex Trauma Network to ensure that patients with certain categories of major injury, who are managed initially in a trauma unit or local receiving hospital, are rapidly transferred to the Major Trauma Centre without delay. The categories of patient to which this applies are: a. Injuries exceed Trauma Unit capabilities b. Pre intubation GCS Motor Score 4 or Less AND evidence from CT of intracranial bleeding (any variant) c. Life threatening haemorrhage not amenable to control at Trauma Unit d. Successful resuscitative thoracotomy at Trauma Unit These patients fulfill automatic acceptance criteria for transfer to the MTC. At the Trauma Unit the senior doctor will call the Ambulance Service and state that they have a “Time Critical Trauma Transfer”. The Trauma Unit Team Leader will then inform the Major Trauma Centre via the red phone in the Emergency Department and state that there is a “Secondary Trauma Transfer”. When prompted the Trauma Team Leader will give an extended ATMIST summary of patient. • NOTE: Do not negotiate terms of admission to UHS with the Trauma Unit. The transfer tool has been specifically written to ensure automatic acceptance by the MTC. The phone call from the Trauma Unit is purely to alert the MTC rather than to seek permission for the transfer. NOTE: Any paediatric secondary transfer referrals must go via SORT (02380 775502) who will not only coordinate the transfer but also give valuable clinical advice and assistance by phone to the Trauma Unit. http://www.sort.nhs.uk/home.aspx 22 Figure 4. Major Trauma Automatic Acceptance Tool (2020) 23 After receiving a secondary trauma transfer pre-alert, the optimum response is to activate a full Level 1 Trauma Call when the patient arrives. It is expected that these patients will have a management plan in place before arrival at UHS and should move swiftly from ED to their destination. Secondary Transfer due to Pre-intubation Motor Score 4 or less • Contact Neurosurgery SpR and Site Manager • Obtain plan from Neurosurgery – Critical Care bed or direct to Theatre • Site manager to arrange Level 3 Bed - Preference NICU > GICU > CICU • Site Manager to discuss with NICU Consultant regarding patient moves if NICU is full • Site Manager to ensure relevant ICU resident medical team and Neurosurgical registrar aware of location of bed if going direct to ICU Secondary Transfer due to Life Threatening Haemorrhage • When Trauma Team arrive, brief that this is a secondary transfer, review imaging with relevant teams and plan for patient’s arrival. This may include activating Theatre or Interventional Radiology teams • Patient will go to ED Resus on arrival unless exact cause of haemorrhage known and time to prepare theatre/Interventional Radiology prior to arrival • Any decision to Bypass ED Resus is only to be made by a Consultant Team Leader Secondary Transfer due to Successful Resuscitative Thoracotomy • Inform Cardiothoracic SpR (Bleep 9211) and Site Manager • Cardiothoracic team should prepare to receive patient in Theatre. Cardiothoracic SpR to inform Consultant, activate theatres and Anaesthetist/ Perfusionist • Site manager to arrange Level 3 Bed, preference Cardiac > General > Neuro • The initial destination in UHS, ED Resus versus cardiac/thoracic theatres may need to be decided on a case by case basis by the TTL. 24 2 Section 2: Trauma Resuscitation ( ABCDE) 2.1 Catastrophic Haemorrhage Recognition and management of catastrophic haemorrhage is the first priority in trauma resuscitation. Catastrophic haemorrhage is poorly defined and simply describes bleeding that is imminently life threatening. Major haemorrhage is variously defined as: • Loss of more than one blood volume in 24 hours • Loss of 50% total blood volume in less than 3 hours • Bleeding in excess of 150ml/min A clinical based approach to defining major haemorrhage is any bleeding which results in a systolic BP 110 bpm. Pre-hospital management focuses primarily on the prevention of further blood loss and the active management of hypothermia and hypoperfusion to prevent Trauma Induced Coagulopathy (TIC). • Tranexamic Acid (TXA) should be given within three hours of injury • Minimal non-haematological fluids should be administered to maintain a central pulse • Blood is available in the pre-hospital setting via HEMS and the Air Ambulances • Tourniquets may be applied in the pre-hospital setting for the management of catastrophic limb haemorrhage 25 Non-torso Catastrophic Haemorrhage Figure 5. Management of Non-torso Catastrophic Haemorrhage 1. Direct signs of vascular injury – pulsatile haemorrhage, expanding haematoma, absence of pulse / ischaemic limb, bruit, palpable thrill, Indirect signs of vascular injury – observed pulsatile bleeding, decreased pulse, nonexpanding haematoma, injury to adjacent nerve, anatomical location of injury near vessel 2. Vascular surgery input should be obtained prior to any imaging if there are direct signs of vascular injury. This can be via the registrar bleep (1322) between 0800 and 1900 and via switch for the on-call consultant after 1900. 3. CT angiography should be undertaken in all cases of suspected vascular injury unless a. There is active haemorrhage b. There is a tourniquet in situ c. Management of other injuries have taken precedence over a controlled vascular injury Discussion with vascular surgery should follow if there is injury to a named vessel which requires surgical management i. Isolated vascular injuries at or distant to the antecubital fossa (ACF) should be referred to Plastic Surgery at Salisbury District Hospital ii. Polytrauma patients with vascular injury at or distant to the ACF should be discussed with Plastic Surgery at UHS 8am – 6pm seven days a week; 6pm – 8am seven days a week these cases should be discussed with Plastic Surgery at Salisbury 4. Pressure should be applied for at least 10 minutes but ideally 20 directly over the wound using sterile gauze. If the bleeding clearly has no prospect of being controlled in the context of a junctional injury then proceed immediately to theatre 5. CeloxTM gauze (Section 4.1) 26 6. Trauma team to transfer patient to theatre for ongoing resuscitation Tourniquets Tourniquets may be required to control life threatening limb haemorrhage. The Wessex Major Trauma Network has an agreed SOP for the use of tourniquets in the pre-hospital and hospital setting (Section 5.1). Apply direct pressure and elevate Apply haemostatic dressing and blast / Oleas bandage and keep direct No pressure on for 5 minutes Successful? Yes Successful? No Observe wound closely for Yes recurrence of bleeding and continue assessment of the patient Apply Tourniquet 5cm proximal to the bleeding wound, if pneumatic, inflate up to 180mmhg – 200mmhg Time tourniquet applied indicated on the label if available. Clearly document in the patient record the time and application of the tourniquet Refer to TUB tool and transfer appropriately Pre alert receiving hospital and advise patient with Tourniquet applied being transferred On arrival at hospital clearly inform the receiving team of the presence of the tourniquet and the time of application Figure 6. Pre-hospital Tourniquet Use 27 A TOURNIQUET INSITU IS NOT A STABLE SITUATION AND REQUIRES URGENT INTERVENTION Advised by Pre hospital team to expect a transfer with tourniquet in situ Yes Position Pneumatic tourniquet, if available (box 1), take down pre hospital dressing, reassess wound. No Can Tourniquet be released? Yes Is Bleeding No controlled? No Apply celox gauze and blast / Oleas bandage Yes Level 1Trauma call raised Are patients ABC stable on Primary Survey? No Inflate Pneumatic tourniquet if available if not reapply tourniquet Ensure a robust plan is in place to release tourniquet for 10 mins every 2hours to allow limb to re-perfuse (box 2) Contact Theatre coordinator on bleep 2894 to obtain pneumatic Tourniquet Consider early activation on Major Hameorrhage protocol Optimise patients Coagulation • 1g TXA bolus • 1g TXA infusion over 8 hours • Reverse Anticoagulation • Keep Ionised Calcium > 1mmol//l • Warm patient to normothermia • TEG to guide coagulation (if available) • Resuscitate to permissive hypotension • Activate and transfuse in accordance with the major hemorrhage protocol Plan to take patient from resus directly to theatre for surgery – Consider Vascular Surgery input Is Bleeding controlled? Yes Observe wound closely for recurrence of bleeding and continue assessment of the patient Box 1 Pneumatic Tourniquet should be placed above the CAT before removing the CAT. Remove the CAT, if bleeding recurs and cannot be controlled by direct pressure, inflate the pneumatic tourniquet. If no longer bleeding, leave pneumatic tourniquet in place, but deflated until definitive decision made about destination of patient Figure 7. In-hospital Tourniquet Use Box 2 –Release of Tourniquet Limb is acutely ischaemic as soon as the tourniquet is applied and ATP stores deplete. Tourniquet should be released for a minimum of 10 mins every 2 hours to allow period of reperfusion. This is in order to reduce the risk of irreversible microvascular injury. Risks with release of tourniquet. • Potentially fatal arrhythmia • Increased PaCO2 and lactate • Increased intracranial pressure • Severe pain • Compartment syndrome • Rhabdomyolysis 28 Cavity Catastrophic Haemorrhage Evidence of cavity catastrophic haemorrhage (persistent hypotension and/or tachycardia presumed secondary to cavity blood loss) that cannot be stabilized in ED Resus requires urgent definitive control via Surgical or Interventional Radiology means. This requires a timely discussion between the TTL, Interventional Radiologist, and relevant Surgical Consultants. Further detail can be found in Section 2.4 Circulation. Massive haemorrhage in the presence of haemodynamic instability should prompt consideration of calling in the oncall Consultant for the cavity of concern. This should be done as soon as possible, and may be considered based on the pre-hospital information received. The decision to go straight to Theatre, either bypassing Resus on arrival or bypassing CT, carries great risk, particularly as the Theatre Suite is not located in close proximity to the ED. This decision must only be taken after consultation between the Team Leader and the relevant Surgical and Anaesthetic Teams. CODE RED Patients with life threatening haemorrhage require urgent replacement of lost circulating volume with blood products. Code Red refers to the activation of the UHS massive transfusion policy (Figure 8 & Section 4.2). Rapid transfusion of blood products is achieved via the Belmont Rapid Infuser (Section 3.2). This is an extremely powerful rapid transfuser which, left unchecked, can deliver huge volumes of blood/fluids within an extremely short period of time e.g. 750ml/minute. The default is to administer repeated boluses (e.g. 250 ml) with regular reassessment of the patient. The CODE RED nurse will be in charge of the Belmont and is also responsible for ensuring an accurate running total of the volume and type of fluids / blood products administered. They should regularly liaise with the Anaesthetist and Team Leader as to ongoing requirements. The benefits of the Belmont include the ability to transfuse when disconnected from a power source but the Belmont will not heat fluids whilst running on battery power and the rate will be reduced to 50ml/minute. 29 Suspected Major Haemorrhage (MH) Action Send G+S to transfusion lab Activate CODE RED (pick up the MH red phone OR call 2222 and state ‘Major Haemorrhage’) Request Pack 1 Allocate staff member/ Code Red practitioner to coordinate transfusion activity Make plan to stop bleeding: Consider splinting, tourniquets, contacting on-call Surgeons (general surgeon bleep 9990) Endoscopist or Interventional Radiologist via switchboard Give Tranexamic acid 1g IV stat bolus dose, followed by 1g over 8 hours infusion. Ensure reversal of anti-coagulants: Warfarin: Octaplex 30iu/kg + give Vit K 10mg IV Heparin: Protamine 6U Blood: Major Haemorrhage Pack 1 Group O from nearest fridge (O-ve for women, O+ve for men) or type specific/cross matched blood from lab (dictated by urgency) Pre-thawed (type A until group specific available) available in ED for ED patients or from the Blood Transfusion Laboratory Request Major Haemorrhage Pack 2 Aims of Transfusion Haemodynamic Stabilisation Hb > 80g/l Platelet count > 75x109/l (> 150x109/l in CNS trauma) INR and APTT ratio 2 Keep iCa2+ above 1.1mmol/l with calcium chloride (starting adult dose 10ml of 10%) Temp > 36oC pH > 7.2 Lactate 13kPa Aim PaCO2 4.5-5kPa Aim MAP > 90mmHg (CPP > 60mmHg if ICP monitored) Maintain normothermia Loading with 1g IV Phenytoin should be considered In addition, the patient’s neck should be in a neutral position and the cervical collar checked to ensure venous outflow is not obstructed. Loosen cervical collar in intubated patients while keeping the head immobilised (e.g sand bags and tape). NOTE: In the absence of hypotension the whole bed should be placed on a 300 head up tilt for patients with severe head injury. This simple manoeuvre47 can significantly help in reducing raised intracranial pressure. Scoop stretchers are for extrication of patients and are used to facilitate transfers. They are uncomfortable and present a significant risk of pressure damage for all patients but particularly those with spinal cord injuries. NOTE: It is the responsibility of the team leader to ensure that the scoop stretcher or spinal boards are removed as soon as possible. Mannitol & Hypertonic Saline The European Brain Injury Consortium and the Brain Trauma Foundation recommend the use of mannitol as the osmotic drug of choice in brain injured patients. Mannitol reduces intracranial pressure within a few minutes. Patients with 1 or 2 fixed & dilated pupils, which is felt to be due to raised intracranial pressure, should receive an IV bolus of either • 10% Mannitol 1g/kg (10ml/kg 10% Mannitol), or • 2.7% saline 6ml/kg Traumatic Brain Injury: Ventilated Patients www.neuroicu.org.uk for up to date guidance. Rapid assessment including pupils and monitoring parameters. Airway Breathing Circulation Disability Environment ET tube type & length at lips; EtCO2 monitoring FiO2; RR; Tidal Volume; Bilateral air entry & SpO2 > 97% HR; BP (MAP > 90mmHg); Presence and positioning of arterial line Pupils (remove contact lenses); Sedation; ?Muscle relaxation Temperature; Glucose Ensure adequate sedation and determine level of pre-existing neuromuscular blockade using a Nerve stimulator/ TOF device. All patients should be assumed to have an unstable spinal injury unless the spinal algorithm (Figure 16) has been completed and Consultant Radiologist report confirms the absence of any acute spinal injury. Transfer patient onto Neuro ICU bed maintaining spinal alignment. • Patient should be placed in a hard cervical collar • Transfer of patient will require spinal turns or the use of a scoop stretcher • 30o head up tilt of whole bed Follow Intracranial Injury Pre-transfer Checklist (Figure 15). 48 Figure 15. Intracranial Injury Pre-transfer Checklist 49 Traumatic Brain Injury: Self-ventilating Patients www.neuroicu.org.uk for up to date guidance. Rapid assessment including pupils and monitoring parameters. Airway Breathing Circulation Disability Maintained and clear; No signs of upper airway obstruction Adequate rate and depth of respiration with Sp
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ACCORD-2 master protocol

Description: CONFIDENTIAL ACCORD-2-001 – Master Protocol TITLE PAGE 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 Master Protocol Number: ACCORD-2-001 Product: Multiple candidate agents 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): IRAS Number: RHM Number: EudraCT 2020-001736-95 282769 Date of Protocol: 22 April 2020 Version: Final Final, 22 April 2020 1 CONFIDENTIAL Chief Investigator Signatory: ACCORD-2-001 – Master Protocol I have read this protocol in its entirety and agree to conduct 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-2-001 – Master Protocol TABLE OF CONTENTS TABLE OF TABLES...............................................................................................................6 TABLE OF FIGURES.............................................................................................................7 1.0 PROTOCOL SUMMARY ..........................................................................................8 1.1 Synopsis.............................................................................................................8 1.2 Schema ............................................................................................................13 1.3 Example Schedule of Activities.....................................................................14 2.0 INTRODUCTION......................................................................................................18 2.1 Study Rationale ..............................................................................................18 2.2 Background ....................................................................................................18 2.3 Benefit/Risk Assessment ................................................................................19 3.0 OBJECTIVES AND ENDPOINTS ..........................................................................20 4.0 STUDY DESIGN........................................................................................................22 4.1 Overall Design ................................................................................................22 4.2 Scientific Rationale for Study Design...........................................................24 4.3 Justification for Dose .....................................................................................24 4.4 End of Study Definition .................................................................................24 5.0 STUDY POPULATION ............................................................................................25 5.1 Inclusion Criteria ...........................................................................................25 5.2 Exclusion Criteria ..........................................................................................25 5.3 Lifestyle Considerations ................................................................................26 5.4 Screen Failures ...............................................................................................26 6.0 STUDY TREATMENT .............................................................................................27 6.1 Study Treatment(s) Administered................................................................27 6.2 Preparation/Handling/Storage/Accountability ...........................................27 6.3 Measures to Minimise Bias: Randomisation and Blinding ........................28 6.4 Study Treatment Compliance.......................................................................28 6.5 Concomitant Therapy....................................................................................28 6.5.1 Rescue Medicine ...............................................................................29 6.6 Dose Modification ..........................................................................................29 6.7 Treatment after the End of the Study ..........................................................29 7.0 DISCONTINUATION OF STUDY TREATMENT AND PATIENT DISCONTINUATION/WITHDRAWAL ................................................................30 7.1 Discontinuation of Study Treatment ............................................................30 Final, 22 April 2020 3 CONFIDENTIAL ACCORD-2-001 – Master Protocol 7.2 Patient Discontinuation/Withdrawal from the Study.................................30 7.3 Lost to Follow-up ...........................................................................................30 8.0 STUDY ASSESSMENTS AND PROCEDURES ....................................................32 8.1 Efficacy Assessments .....................................................................................33 8.1.1 Improvement on the 9-Point Scale ....................................................33 8.1.2 Other Efficacy Assessments ..............................................................34 8.2 Safety Assessments.........................................................................................34 8.2.1 Physical Examinations.......................................................................34 8.2.2 Vital Signs and Blood Gases .............................................................34 8.2.3 Clinical Safety Laboratory Assessments ...........................................35 8.3 Virologic Load ................................................................................................35 8.4 Adverse Events ...............................................................................................35 8.4.1 Time Period and Frequency for Collecting AE and SAE Information ........................................................................................35 8.4.2 Method of Detecting AEs and SAEs .................................................36 8.4.3 Follow-up of AEs and SAEs .............................................................36 8.4.4 Regulatory Reporting Requirements for SAEs .................................36 8.4.5 Pregnancy ..........................................................................................37 8.4.6 Adverse Events of Special Interest ....................................................37 8.4.7 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as Adverse Events or Serious Adverse Events.........37 8.5 Treatment of Overdose..................................................................................37 8.6 Pharmacokinetics ...........................................................................................37 8.7 Pharmacodynamics........................................................................................38 8.8 Immunology....................................................................................................38 8.9 Genomics.........................................................................................................38 8.10 Serology Research (Host Response) .............................................................39 9.0 STATISTICAL CONSIDERATIONS .....................................................................39 9.1 Design Overview.............................................................................................39 9.2 Statistical Hypotheses ....................................................................................39 9.3 Sample Size Determination ...........................................................................40 9.4 Populations for Analyses ...............................................................................42 9.5 Statistical Analyses.........................................................................................42 9.5.1 Efficacy Analyses ..............................................................................43 9.5.2 Safety Analyses .................................................................................43 9.5.3 Other Analyses ..................................................................................44 9.5.4 Missing Data......................................................................................44 9.6 Interim Analyses ............................................................................................45 9.7 Review Committees........................................................................................45 9.7.1 Steering Committee (Scientific Review Committee) ........................45 9.7.2 Independent Data and Safety Monitoring Committee.......................45 Final, 22 April 2020 4 CONFIDENTIAL ACCORD-2-001 – Master Protocol 10.0 REFERENCES...........................................................................................................47 11.0 APPENDICES ............................................................................................................48 Appendix 1 Abbreviations ...................................................................................49 Appendix 2 Regulatory, Ethical, and Study Oversight Considerations..........51 Protocol Compliance........................................................................................51 Regulatory and Ethical Considerations............................................................51 Financial Disclosure.........................................................................................52 Indemnity .........................................................................................................52 Informed Consent Process ...............................................................................52 Data Protection.................................................................................................53 Administrative Structure ..................................................................................54 Dissemination of Clinical Study Data..............................................................54 Data Quality Assurance ...................................................................................54 Source Documents ...........................................................................................55 Study and Study Centre Closure ......................................................................55 Publication Policy ............................................................................................56 Appendix 3 Clinical Laboratory Tests ...............................................................57 Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting .....................................59 Appendix 5 Collection of Pregnancy Information ............................................63 Appendix 6 Genetics ............................................................................................65 Appendix 7 Signature of Investigator ................................................................66 Final, 22 April 2020 5 CONFIDENTIAL ACCORD-2-001 – Master Protocol Table 1 Table 2 Table 3 Table 4 Table 5 TABLE OF TABLES Study Objectives and Endpoints ......................................................................20 Sample Size for 80% and 90% Power for Time to Improvement, Discharge from Hospital, or Fit for Discharge Using Log-rank Test for a Hazard Ratio of 1.6 in Treatment Arm to Standard of Care ...................41 Analysis Sets ....................................................................................................42 Efficacy Analyses ............................................................................................43 Protocol-required Safety Laboratory Assessments..........................................58 Final, 22 April 2020 6 CONFIDENTIAL ACCORD-2-001 – Master Protocol Figure 1 TABLE OF FIGURES Study Schema...................................................................................................13 Final, 22 April 2020 7 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.0 PROTOCOL SUMMARY 1.1 Synopsis 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 Rationale: There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death Final, 22 April 2020 8 CONFIDENTIAL ACCORD-2-001 – Master Protocol Secondary • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • 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. • To evaluate the number of oxygen-free days. • Duration (days) of oxygen use and oxygen-free days. • To evaluate ventilator-free days and incidence and • Duration (days) of ventilation and ventilation-free duration of any form of new ventilation use. days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • To evaluate SARS-CoV-2 viral load. • 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 • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, 22, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Final, 22 April 2020 9 CONFIDENTIAL ACCORD-2-001 – Master Protocol Exploratory • To evaluate SARS-CoV-2 viral load. • 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). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Overall Design: ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised – mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub-protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require equivalent blood samples from controls). The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the Final, 22 April 2020 10 CONFIDENTIAL ACCORD-2-001 – Master Protocol study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe adverse events (AEs), overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. Number of Investigators and Study Centres: Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Number of Patients: The expected number of patients for each treatment arm is presented as part of the sample size determination below. It is estimated that up to 1800 patients will participate in the overall study. Treatment Groups and Duration: In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Statistical methods: Sample size determination: Stage 1: Based on the chosen endpoint, a preliminary analysis will be carried out when an estimated 81 events have been observed across each agent treatment and SoC or 28 days after the last patient has been randomised, whichever occurs sooner, as determined by the Independent Data and Safety Monitoring Committee (IDMC). In order to achieve this number of events, it is expected that 54 patients are needed per arm, which will provide 80% power to detect a hazard ratio of 1.6 for the occurrence of the event, when comparing each candidate agent with SoC. To allow for uncertainty in the recruitment rates, it is expected that up to 60 patients will be randomised to each arm in order to achieve the required number of events for the preliminary analysis. Stage 2: The number of patients will be determined more precisely at the end of Stage 1, but approximately 126 patients will be randomised to each arm. Analysis sets: • Intention to Treat (ITT): All patients who are randomised and match the inclusion/exclusion criteria of the Master Protocol and relevant sub-protocol will be included in the ITT. • Safety Set: All patients who are randomised and take at least 1 dose of study medication will be included in the safety set. Final, 22 April 2020 11 CONFIDENTIAL ACCORD-2-001 – Master Protocol • Pharmacokinetic Analysis Set (PKS): All patients who are randomised and take at least 1 dose of the candidate agent and have quantifiable candidate agent concentrations postdose without protocol deviations or events affecting the pharmacokinetic results will be included in the PKS. • Pharmacodynamic Analysis Set (PDS): All patients who are randomised and take at least 1 dose of study medication (candidate agent or SoC) and have evaluable results for at least 1 pharmacodynamic endpoint postdose. All analyses of the PDS will be based on each patient’s randomised assigned treatment (not actual treatment received). Efficacy, safety, pharmacokinetic, and pharmacodynamic results will be listed and summarised by stage, dose, and scheduled time for the respective analysis sets, where appropriate. Candidate agent concentration versus response variables may be graphically displayed for selected endpoints. Exposure-response data obtained from this study may be combined with data from other studies and used for modelling and simulations. Data Monitoring Committee: A Steering Committee will evaluate interim analysis data to make decisions on further progression of the candidate agents within the study, and will provide guidance, advice, and recommendations to the ACCORD program on relevant clinical issues related to the strategy, implementation, and conduct of the study. An IDMC will objectively monitor safety data throughout the study to make recommendations to the Steering Committee regarding study conduct. Final, 22 April 2020 12 CONFIDENTIAL 1.2 Schema Figure 1 Study Schema ACCORD-2-001 – Master Protocol IA=interim analysis; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SoC=standard of care. Note: This figure shows a hypothetical situation, where in Stage 1 of the study there are 4 candidate agents being compared with the SoC, of which 2 candidate agents progress to Stage 2. Final, 22 April 2020 13 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.3 Example Schedule of Activities Screening Baseline Day (± Window) ELIGIBILITY Informed consent Demographics Relevant medical historyb Review of SARS-CoV-2 diagnostic tests Inclusion and exclusion criteria 12-lead Electrocardiogram STUDY INTERVENTION Randomisation Administration of candidate agent 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) Vital signs, including oral temperature, pulse rate, blood pressure, respiratory rate, SpO2 Day -1 or Day 1 X X X X X X X X X Day 1 X X Xc Daily Until Hospital Discharge Day 15a (±2 days) Defined in subprotocol X X X X Day 29a (±3 days) X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Final, 22 April 2020 14 CONFIDENTIAL ACCORD-2-001 – Master Protocol Screening Baseline Day (± Window) Clinical assessmentsd 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 PO2e SAFETY LABORATORY Haematology, chemistry, liver function tests, coagulationf Day -1 or Day 1 X Xg Day 1 Xc Xc X X X X Xc,h Pregnancy test for females of childbearing potential Xg RESEARCH LABORATORY Blood (SST) for exploratory inflammatory cytokine analysis X (others to be defined in sub-protocols) Blood (sodium heparin tube) for PBMC phenotypingi X Blood (EDTA) for SARS-CoV-2 PCR (qualitative and quantitative) X Daily Until Hospital Discharge X X X X X X Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 8 Day 8 Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 15a (±2 days) X X X X X X X X Day 29a (±3 days) X X X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) X X X X X X X X Final, 22 April 2020 15 CONFIDENTIAL ACCORD-2-001 – Master Protocol 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) Oropharyngeal/nasal swab for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Saliva for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Blood (SST) for SARS-CoV-2 serology research (host response) X Day 8 X X X Blood (PAXGENE) for transcriptome analysis (host genome)j X Day 8 X Blood (EDTA) host genome (host DNA)j X Mid-turbinate nasal swab viral genomej X EDTA=ethylenediaminetetraacetic acid; FiO2=fraction of inspired oxygen; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; 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. Note: Additional assessments, if required, will be defined in the sub-protocol. 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). c Baseline assessments should be performed prior to study drug administration. d 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. e If done as part of SoC, blood gases results to be fully recorded with date and time. f For parameters, see Table 5. Final, 22 April 2020 16 CONFIDENTIAL ACCORD-2-001 – Master Protocol g Laboratory tests performed in the 48 hours prior to enrolment will be accepted for determination of eligibility. h Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. i Samples collected for immediate laboratory processing and frozen storage. j Samples collected dependent on capacity of study centre, need for reduced study burden on staff, and potentially limited access to patients. Final, 22 April 2020 17 CONFIDENTIAL ACCORD-2-001 – Master Protocol 2.0 INTRODUCTION 2.1 Study Rationale There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. 2.2 Background Coronaviruses are single-stranded RNA viruses, capable of causing life-threatening disease in humans and animals. The novel coronavirus SARS-CoV-2 was initially identified during an outbreak of viral pneumonia cases of unknown cause in China. Most of the initial infections outside of China were travel associated (ie, from people who had travelled from the infected regions of China to other countries), although person-to-person transmission in other countries was quickly established. The disease caused by the SARS-CoV-2 virus has been designated COVID-19. SARS-CoV-2 binds via the angiotensin-converting enzyme (ACE) receptor located on alveolar cells and intestinal epithelia.1 The virus is mutating, indicating that virulence and transmission will shift over time, and showing diversity in critical surface protein. New evidence suggests there are 2 groups of SARS-CoV-2; L-type and S-type.2 S-type is the less aggressive (30%); the L-type is now the most prevalent version (70%) and is more aggressive. Additionally, individuals appear to be affected to different degree with varying symptoms and outcomes. These findings strongly support an urgent need for immediate comprehensive studies and robust validation of testing methods that combine genomic data, chart records and clinical symptoms, to help better understand the disease, enable risk assessment, triage and support public health resource planning. Due to the rapid global widespread of SARS-CoV-2, there is an urgent need to develop efficacious treatments for the disease. Current clinical studies involve the use of already approved medications for other indications (repurposing) where it is thought that they might also be effective in the treatment of COVID-19 disease, as well as development of antibody-based therapies against the virus. Final, 22 April 2020 18 CONFIDENTIAL ACCORD-2-001 – Master Protocol This platform study will test multiple candidate agents, with the aim of identifying potentially efficacious treatments in the shortest timeframe possible. In addition, it will support secondary research objectives that are critical for understanding the disease, spread of infection and robust tests to track it. 2.3 Benefit/Risk Assessment There are currently no approved therapeutic agents available to treat coronaviruses such as SARS-CoV-2, and so while there may not be benefits for an individual patient participating in this study, there may be benefits to society if a safe and efficacious therapeutic agent can be identified during the global COVID-19 outbreak. Detailed information about the known and expected risks and reasonably expected adverse events (AEs) of each candidate agent may be found in the corresponding sub-protocol for that agent. Final, 22 April 2020 19 CONFIDENTIAL ACCORD-2-001 – Master Protocol 3.0 OBJECTIVES AND ENDPOINTS Table 1 Study Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Secondary • 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. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death • 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 Final, 22 April 2020 20 CONFIDENTIAL ACCORD-2-001 – Master Protocol • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Exploratory • To evaluate SARS-CoV-2 viral load. • 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). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Final, 22 April 2020 21 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.0 STUDY DESIGN 4.1 Overall Design ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or validated point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised - mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale, which was detailed in the World Health Organization R&D Blueprint “Novel Coronavirus - COVID-19 Therapeutic Trial Synopsis” (February 2020). Medical history will record the estimated date and time of first symptoms. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. A Steering Committee will evaluate candidate agents for progression in the study (see Section 9.7.1). This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require Final, 22 April 2020 22 CONFIDENTIAL ACCORD-2-001 – Master Protocol equivalent blood samples from controls). Additional patients will be recruited into the study each time a new sub-protocol (candidate agent) is added. The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe AEs, overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. It is estimated that up to 1800 patients will participate in the overall study. Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Final, 22 April 2020 23 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.2 Scientific Rationale for Study Design There are currently no approved therapeutic agents available to treat coronaviruses such SARS-CoV-2, the causative agent of as COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. This study utilises an adaptive design that maximises efficiency in identifying a safe and efficacious therapeutic agent for COVID-19. Some candidate agents may be in limited supply and this study design enables continuation of the study even if an agent becomes unavailable. In addition, the adaptive design allows for the evaluation of new candidate agents as they are identified. 4.3 Justification for Dose Justification for the dose of each candidate agent will be included in the corresponding sub-protocol. 4.4 End of Study Definition For each sub-protocol, the end of the study for that candidate agent will be defined as the date on which the last patient completes the last visit for that sub-protocol. For the overall study, the end of the study will be defined as the date on which the last patient completes the last visit for the final sub-protocol to be concluded. Once a patient has completed this study, there are no restrictions on them entering another study, subject to the eligibility criteria of that subsequent study. Final, 22 April 2020 24 CONFIDENTIAL ACCORD-2-001 – Master Protocol 5.0 STUDY POPULATION Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol waivers or exemptions, is not permitted. The inclusion and exclusion criteria listed below may be supplemented by additional criteria stipulated in the sub-protocols that are specific to the target candidate being tested (eg, criteria related to prohibited medications). In order to enrol, a patient or legally authorised representative must sign an informed consent form (ICF) and meet all entry criteria for both the Master Protocol and at least 1 respective sub-protocol. 5.1 Inclusion Criteria Patients are eligible to be included in the study only if all of the following criteria apply (as well as all criteria from the appropriate sub-protocol): 1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or point of care tests. 2. A score of Grade 3 to 5 on the 9-point ordinal scale. 3. Is a woman who is not of childbearing potential (as defined in Appendix 5) or The patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study and for at least 6 weeks after termination of study therapy. 4. Ability to provide informed consent signed by the study patient or legally authorised representative. 5.2 Exclusion Criteria Patients are excluded from the study if any of the following criteria apply (or any of the criteria from the appropriate sub-protocol): 1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale. 2. Any patient whose interests are not best served by study participation, as determined by a senior attending clinician. 3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 5 × the upper limit of normal (ULN). 4. Known active infection with HIV or hepatitis B or C. 5. Stage 4 severe chronic kidney disease or requiring dialysis (ie, estimated glomerular filtration rate 500 ms. 8. Anticipated transfer to another hospital that is not a study centre within 72 hours. 9. Allergy to any study medication. 10. Experimental off-label usage of medicinal products as treatments for COVID-19. 11. Patients participating in another clinical study of an investigational medicinal product. 5.3 Lifestyle Considerations Any lifestyle considerations that are specific to the candidate agent will be defined in the corresponding sub-protocol. Female patients are advised to avoid becoming pregnant during the study. 5.4 Screen Failures Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently randomly assigned to study treatment. A minimal set of screen failure information is required to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). Individuals who do not meet the criteria for participation in this study (screen failure) due to hypokalaemia, hypomagnese
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Clinical case tutorial key learning points

Description: Auto Generated Title Hypothyroidism is an important secondary cause of hyperlipidaemia and should always be screened for in patients presenting with significant lipid levels. In this patient, thyroid function should first be optimised and fasting lipids repeated before CVD risk is undertaken. Familial causes should also be excluded if the levels are still high after thyroxine treatment. Other common secondary causes of dyslipidaemia include excessive alcohol intake, poor diet, chronic liver and kidney disease and drugs. All patients with lipid problems need advice on lifestyle changes.
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BEACON protocol v8.0 07Mar2023 signed

Description: A randomised phase IIb trial of BE AC v izumab added to Temozolomide O ± Irin tecan for children with N refractory/relapsed euroblastoma Version 8.0 dated 07-Mar-2023 Dinutuximab beta amendment Coordinating Sponsor: Sponsor Protocol Number: CAS Code: EudraCT Number: ISRCTN Reference Number: ITCC Number: Roche Study Reference Number: Email: University of Birmingham RG_ 11-087 BN2008 2012-000072-42 40708286 032 MO28245 beacon@trials.bham.ac.uk This application is supported by the facilities funded through Birmingham Science City: Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project which forms part of the Science City University of Warwick and University of Birmingham Research Alliance. BEACON-Neuroblastoma Protocol_vn 8.0_vd 07Mar2023 Page1 of 157 BEACON-Neuroblastoma Trial Protocol AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version Amendment Date of number amendment Protocol version number Type of amendment SA 1 29-Jan-2013 2.0 Substantial Amendment N/A 23-Apr-2013 2.0a Non-Substantial Amendment N/A 01-Jul-2013 2.0b Non-Substantial Amendment Summary of amendment Introduction of the recommendation of weekly monitoring of blood counts for all patients receiving irinotecan. Addition of planned vaccination with live vaccination to exclusion criteria and prohibited medications section. ITCC Number has been corrected. Roche Study Reference Number and ISRCTN Reference Number have been added. Contact details for Plasma & Tumour Angiogenesis-Related Biomarkers have been amended. Table numbers have been corrected. Addition of guidance for research bone marrow sampling in Schedule of Activities table and sections 7.4.2.2 and 7.5.2. Addition of paragraph to sections 7.2, 7.6.1 – 7.6.4 detailing arrangements for handling dose modifications for Irinotecan + Temozolomide for patients receiving Bevacizumab. Discontinuation rules for osteonecrosis of the jaw and eye disorders added to table 13 in section 7.6.4. Correction to table number references in section 7.6.3. Clarification made in section 13.4.1 concerning Planned Interim Analysis. SA 3 06-Oct-2014 4.0 Substantial Amendment Changes to the Trial Personnel section of the protocol to include the addition of contact details for Denmark and Ireland Lead Investigators. Amendments to reflect the changes in study sampling requirements to Trial Synopsis, Schedule of Activities table and sections 1.2.6, 2.1, 2.2, 5.1, 5.2, 7.3, 7.4.2 and 7.5. Amendment to exclusion criteria in Trial Synopsis and section 4.2. Changes to the Schedule of Activities table to include the addition of an echocardiogram to be performed at screening and Tanner staging at screening and yearly in follow up. Changes to the time line for measuring renal function prior to commencing treatment in the Trial Synopsis, Schedule of Activities and section 4.1. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 3 of 157 BEACON-Neuroblastoma Trial SA 4 06-Oct-2014 4.0 SA 5 30-Jul-2015 5.0 Substantial Amendment Substantial Amendment Protocol Option to fax emergency randomisation removed. Telephone only in section 6.2 Changes to guidelines in section 7.2 for dose calculation in patients whose weight exceeds the 98th centile for age. Removal of enhanced data collection for Adverse Events of Special Interest (AESI) in section 7.6 and 9.1.2. Addition of option to extend treatment delay with agreement from Sponsor in Section 7.6.1 Addition of necrotising fasciitis as an adverse event requiring bevacizumab discontinuation in section 7.6.4. Changes to section 7.10 concerning the documenting of concomitant medications in patient medical notes and administration of bisphosphonates. Changes to section 9.1 regarding reporting of laboratory adverse events. Clarification on the arrangements for Follow Up Form completion for patients who do not require further follow up visits in section 11. Changes to bevacizumab and irinotecan preparation and dispensing guidelines in sections 8.2.4 and 8.3.3. Clarification on fasting arrangements prior to temozolomide administration added to section 8.4.3. Changes to events that should be reported on an Expected SAR Form in section 9.1.3.1. Clarification on SAEs that should be reported to F.Hoffman-La Roche Ltd in section 9.2.6 Addition of Trial Management Group meeting frequency in section 14.4. Changes to the wording of irinotecan randomisation in section 13.4.2. Addition of guidelines for dose reduction and discontinuation of temozolomide for liver toxicity in tables 8, 9, 10 & 11. Reference to the National Coordinating Centres has been changed to National CoSponsor throughout. Reference to Sponsor has been changed to Coordinating Sponsor. Change of Chief Investigator to Professor Pamela Kearns. Change of Principal Investigator at Royal Marsden Hospital to Dr Sucheta Vaidya. No changes made to the Protocol version. Chief Investigator and UK Lead Investigator changed to Dr Lucas Moreno Switzerland details added Schedule of events table amended for End Of Treatment clarity BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 4 of 157 BEACON-Neuroblastoma Trial N/A 23-Sep-2015 5.0a SA 6 16-Jan-2019 6.0a Protocol Topotecan added to the study as a new trial question and 2 new randomisation arms. The following sections are amended accordingly: Synopsis (Primary Objectives, sample size, Trial Duration, Trial therapy) Section 1 Background and rationale (Trial rationale) Section 3 Trial design (Randomisation) Section7.1 and 7.2 Treatment details Section7.6.1 Dose modifications Table 6 amended, Tables 11 and 12 added Section 8.4 Pharmaceutical Information Section 13 Statistical considerations The following changes were made to the Eligibility: Inclusion criteria – further details regarding birth control Exclusion criteria – Defined wash out period following prior IMP according to IMP half-life or 14 days. Lifestyle guidelines - further details regarding birth control Section 7.6 Dose modifications Figure 1 – reference to “chemo” changed to Temozolomide/Irinotecan/Topotecan” for clarity Section 8.2.4 Reference to “chemo” removed for clarity Section 7.6.4 AEs requiring Bevacizumab discontinuation – additional AEs added following Bevacizumab IB v22 Addendum Additional mRNA and exploratory sampling. Non-Substantial Amendment Substantial amendment The requirement for confirmatory scans was removed from the Schedule of Activities and Response assessment section 7.4.3. Lead Investigator for France amended to Dr Marion Gambart Minor wording corrections and clarifications Schedule of events table corrected Introduction of two new treatment arms (dinutuximab beta) for additional 64 patients Addition of eligibility criteria, schedule of events, treatment details, duration, cross over and dose modification details for new dinutuximab beta arms Adaptation of objectives, trial design, supporting treatment, pharmaceutical information and statistical consideration sections with new, relevant information. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 5 of 157 BEACON-Neuroblastoma Trial N/A 11-Apr-2019 6.0b SA 7 07-Feb-2020 7.0 SA 22 07-Mar-2023 8.0 Protocol Non-Substantial Amendment Substantial Amendment Substantial Amendment Minor wording corrections and clarifications Version amended from 6.0 to 6.0a to add. Additional rationale to update typographical errors.) Trial Synopsis: Clarification of recruitment targets Clarification of Section 10 title: “Dinutuximab beta and topotecan randomisations” Clarification that not all biological studies will be open at any one time (Section 10.2 and 15.5) Minor wording corrections and clarifications Urgent Safety Measure – implemented on 28th January 2020 Closure of Temozolomide (T) and Dinutuximab beta and Temozolomide (dBT) arms with immediate effect. Section 1.1 Background Section 1.2.3 Benefit Risk assessment Section 3.1 Randomisation Section 10 Headings changed Section 10.3 Trial therapy Update of contact details Change of definition of End of Trial (Section 21). Protocol previously defined two stages of end of trial (6 months after last patient completes treatment and 12 months after last data capture after 5 years follow up). This has been combined into one End of Trial definition: 6 months after last patient last visit (i.e. after 5 years follow up) Also addition of option to email SAE form (Section 18.2.1.2) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 6 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL PERSONNEL Chief Investigator: Co-Investigators: Exploratory Biomarkers Dr Lucas Moreno Dr. Lucas Moreno, MD, PhD Director Paediatric Oncology & Haematology Division Vall d’Hebron Barcelona Hospital Campus Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain  +34 93 489 3000  +34 93 489 4060  lucas.moreno@vhebron.net Professor Keith Wheatley Professor of Clinical Trials Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 415 9119  k.wheatley@bham.ac.uk Dr Juliet Gray Associate Professor and Consultant in Paediatric Oncology Southampton Children’s Hospital Tremona Road Southampton SO16 6YD  +44 (0) 790 1507929  juliet.gray@uhs.nhs.uk Dr Gudrun Schleiermacher Senior Scientist Institute Curie 26 rue d'Ulm 75248 Paris cedex 05 France  +33 (0)1 56 24 45 50  +33 (0)1 56 24 66 30  gudrun.schleiermacher@curie.net Professor Louis Chesler Paediatric Tumour Biology Team Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0) 208 722 4035 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 7 of 157 BEACON-Neuroblastoma Trial Protocol  louis.chesler@icr.ac.uk Functional Imaging Study: Professor Andrew Peet Institute of Child Health University of Birmingham Whittall Street Birmingham, UK B4 6NH  +44 (0) 121 333 8234  +44 (0) 121 333 8241  a.peet@bham.ac.uk Dr Dow-Mu Koh Consultant Radiologist in Functional Imaging Royal Marsden Hospital Downs Road, Sutton, Surrey, UK SM2 5PT  +44 (0) 208 6613857  dow-mu.koh@icr.ac.uk Professor Martin Leach Co-Director, Cancer Research UK and EPSRC Centre for Cancer Imaging, Director, NIHR Clinical Research Facility Deputy Head, Division of Radiotherapy and Imaging Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0 208 661 3338  Martin.Leach@icr.ac.uk Molecular Monitoring mRNA Study: Professor Sue Burchill Leeds Institute of Cancer & Pathology St. James University Hospital Beckett Street Leeds, UK LS9 7TF  +44 (0) 113 206 5873  +44 (0) 113 242 9886  S.A.Burchill@leeds.ac.uk Professor Walter Gregory Clinical Trials Research Unit (CTRU) University of Leeds Clinical Trials Research House 71-75 Clarendon Road Leeds LS2 9PH  +44 (0) 113 343 1489  +44 (0) 113 343 1471 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 8 of 157 BEACON-Neuroblastoma Trial Protocol Trial Statistician: Trial Coordinator & Trial Office: Randomisation Service: SAE Reporting:  W.M.Gregory@leeds.ac.uk Miss Grace Holt Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 8328  +44 (0)121 414 3700  G.C.Holt@bham.ac.uk Miss Punam Mistry Children’s Cancer Trials Team Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  beacon@trials.bham.ac.uk Provided by the CRCTU at the University of Birmingham Randomisation should be performed by sites online at: https://www.cancertrials.bham.ac.uk/BEACONLive In case of any problems with online randomisation, randomisation can be performed over the phone by the CRCTU on: 0800 371 969 or +44 (0)121 414 3366 SAEs should be faxed to the BEACON-Neuroblastoma Trial Office, CRCTU, University of Birmingham, UK  + 44 (0)121 414 9520 or +44 (0)121 414 3700 National Coordinating Investigators: Austria – Lead Investigator: Prof Dr Ruth Ladenstein St. Anna Children’s Hospital and CCRI /Studies and Statistics Department for Integrated Research and Projects (S²IRP) Kinderspitalgasse 6, Zimmermannplatz 10 A-1090 Vienna Austria +43-1-40470-4750  +43-1- 40470- 7430  ruth.ladenstein@ccri.at BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 9 of 157 BEACON-Neuroblastoma Trial Belgium Lead Investigator: Prof Genevieve Laureys Ghent University Hospital 9000 Ghent De Pinterlaan 185 Belgium  +32 93 32 34 48  genevieve.laureys@uzgent.be Denmark – Lead Investigator: Dr Karsten Nysom Dept. of Paediatrics & Adolescent Medicine Rigshospitalet Blegdamsvej 9 DK2100 Copenhagen Denmark  +45 35 45 08 09  +45 35 45 50 55  Karsten.nysom@regionh.dk France – Lead Investigator: Dr Marion Gambart Unité d'Hémato-Oncologie Hôpital des Enfants 330, avenue de Grande Bretagne TSA 70034 31059 Toulouse Cedex France  +33 (0)5 34 55 86 11  +33 (0)5 34 55 86 12  gambart.m@chu-toulouse.fr Germany - Lead Investigator: Dr. Simone Hettmer Zentrum für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM FREIBURG Mathildenstr. 1, 79106 Freiburg Germany  +49 761 270-43000  +49 761 270-45180  simone.hettmer@uniklinik-freiburg.de Ireland – Lead Investigator: Dr Cormac Owens Our Lady’s Children’s Hospital Crumlin Road, Crumlin Dublin 12 Ireland  +35314096659  +35313453041  Cormac.owens@olchc.ie Protocol BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 10 of 157 BEACON-Neuroblastoma Trial Protocol Italy – Lead Investigator: Dr. Aurora Castellano U.O.Oncoematologia Ospedale Pediatrico Bambino Gesù Pzza S. Onofrio 4 00165 Roma Italy +39 06 68592957-2678  +39 06 68592826  aurora.castellano@opbg.net Netherlands – Lead Investigator: Dr. C Michel Zwaan Erasmus Medical Center Sophia’s Children's Hospital Dr. Molewaterplein 60 3015 GJ Rotterdam +31 (0) 10 703 6691  +31(0) 10 703 6681  c.m.zwaan@erasmusmc.nl Spain – Lead Investigator: Dr. Victoria Castel Instituto de Investigación Sanitaria Unidad de Oncología Pediátrica Hospital Universitario La Fe Bulevar Sur, S/N 46026 Valencia Spain +34 963862758 Ext 50040  +34 963494416  castel_vic@gva.es Switzerland – Lead Investigator: Dr. Nicolas Gerber University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland +41 44 266 31 17  +41 44 266 34 61  Nicolas.gerber@kispi.uzh.ch UK – Lead Investigator: Dr Lucas Moreno Honorary Research Fellow University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  lucas.moreno@vhebron.net, lmorenom@ext.cnio.es BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 11 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL SYNOPSIS Title A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma – BEACON-Neuroblastoma Trial Trial Design A phase II, randomised, open label, international multicentre 3x2 factorial trial. The dinutuximab beta amendment did utilise a 2x2 factorial design it will now be a simple two-way randomisation. Objectives Primary: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan + temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma - To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma (“topotecan randomisation”) - To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma (“dinutuximab beta randomisation”) Secondary: - To evaluate the safety of the regimens Tertiary: - To undertake preliminary evaluation of the changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis - To undertake preliminary evaluation of the role of circulating mRNA levels for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and doublecortin (DCX) as prognostic/predictive biomarkers in this refractory/relapsed setting - To undertake a preliminary evaluation of the role of tumour molecular profiles in blood and archival tumour tissue profiles as prognostic and predictive biomarkers - To undertake a preliminary evaluation of biomarkers of response to anti-GD2 therapy (Fc/KIR polymorphisms, Antibody Dependant Cell-Mediated Cytotoxicity (ADCC) and Anti-Drug Antibodies (ADAs) and of dinutuximab beta pharmacokinetics (PK) Outcome Measures Primary Endpoint: - Best response (Complete Response [CR] or Partial Response [PR]) [1] at any time during the first 6 cycles of trial treatment - For the bevacizumab part 2 only: Progression-free survival (PFS) Secondary Endpoints: - Safety of the regimens: Incidence and severity of Adverse Events (AE)s - PFS - Overall survival (OS) - Event-free survival (EFS) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 12 of 157 BEACON-Neuroblastoma Trial Protocol Exploratory/Tertiary Endpoints: - Changes in (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2* - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples - Pilot descriptive study of angiogenesis and neuroblastoma markers that may include O6methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling - A preliminary correlation of the different biomarkers [Fc/KIR polymorphisms, Antibody – Dependent Cellular Toxicity (ADCC), and Anti-Drug Antibodies (ADAs)] will be made with parameters of anti-tumour activity (response rate, PFS and OS). PK parameters (dinutuximab beta trough levels) for this chemo-immunotherapy regimen will be described. Patient Population Children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma. Sample Size Approximately 224 patients, including 160 for the bevacizumab randomisation and 64 for the dinutuximab beta amendment. Trial Duration 8 years of patient recruitment, 5 years of patient follow up BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 13 of 157 BEACON-Neuroblastoma Trial Protocol Abbreviations ADA ANTI-DRUG ANTIBODIES ADCC ANTIBODY – DEPENDENT CELL-MEDIATED CYTOTOXICITY AE ADVERSE EVENT AESI ADVERSE EVENT OF SPECIAL INTEREST AFSAPPS COMPETENT AUTHORITY FOR FRANCE ALT ALANINE AMINOTRANSFERASE ANC ABSOLUTE NEUTROPHIL COUNT APPT ACTIVATED PARTIAL THROMBOPLASTIN TIME ASCT AUTOLOGOUS STEM CELL TRANSPLANTATION AST ASPARTATE AMINOTRANSFERASE AUC AREA UNDER THE CURVE AR ADVERSE REACTION BIT BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM BM BONE MARROW BP BLOOD PRESSURE BSA BODY SURFACE AREA BT BEVACIZUMAB + TEMOZOLOMIDE ARM BTTo BEVACIZUMAB + TEMOZOLOMIDE + TOPOTECAN ARM CI CHIEF INVESTIGATOR CIs CONFIDENCE INTERVALS COG CHILDREN’S ONCOLOGY GROUP CNS CENTRAL NERVOUS SYSTEM CR COMPLETE RESPONSE CRF CASE REPORT FORM CR UK CANCER RESEARCH UK CRCTU CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) CRN CLINICAL RESEARCH NETWORK CSR CLINICAL STUDY REPORT CT COMPUTERISED TOMOGRAPHY CTC COMMON TERMINOLOGY CRITERIA CTCAE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS CXR CHEST X-RAY dBT DINUTUXIMAB BETA + TEMOZOLOMIDE ARM dBTTo DINUTUXIMAB BETA + TEMOZOLOMIDE + TOPOTECAN ARM DCX DOUBLECORTIN DLT DOSE LIMITING TOXICITY DMC DATA MONITORING COMMITTEE DNA DEOXYRIBONUCLEIC ACID ECHO ECHOCARDIOGRAM ECOG EASTERN COOPERATIVE ONCOLOGY GROUP EFS EVENT FREE SURVIVAL EMA EUROPEAN MEDICINES AGENCY ERDC ELECTRONIC REMOTE DATA CAPTURE EOT END OF TREATMENT FFPE FORMALIN-FIXED PARAFFIN EMBEDDED GCP GOOD CLINICAL PRACTICE G-CSF GRANULOCYTE COLONY STIMULATING FACTOR BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 14 of 157 BEACON-Neuroblastoma Trial Protocol GFR GM-CSF GGT GP GPOH HR IB ICF ICH IMP INR INRC INRG INSS IRF ISF IT ITCC IV MGMT MIBG MHRA MRD MRI MSKCC MTD MYCN NANT NCI NCS NR OS OTC PCP PD PFS PHOX2B PI PIS PK PMA PRES PO PPTP PR REC RECIST RNA GLOMERULAR FILTRATION RATE GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR GAMMA-GLUTAMYL TRANSPEPTIDASE GENERAL PRACTITIONER GERMAN SOCIETY FOR PAEDIATRIC ONCOLOGY & HAEMATOLOGY HEART RATE INVESTIGATOR BROCHURE INFORMED CONSENT FORM INTERNATIONAL CONFERENCE ON HARMONISATION INVESTIGATIONAL MEDICINAL PRODUCT INTERNATIONAL NORMALISED RATIO INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA INTERNATIONAL NEUROBLASTOMA RISK GROUP INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM INSTITUTIONAL REVIEW BOARD INVESTIGATOR SITE FILE IRINOTECAN + TEMOZOLOMIDE ARM INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER INTRAVENOUS O6-METHYGUANINE METHYLTRANSFERASE META-IODO-BENZYL-GUANIDINE MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY MINIMAL RESIDUAL DISEASE MAGNETIC RESONANCE IMAGING MEMORIAL SLOAN KETTERING CANCER CENTRE MAXIMUM TOLERATED DOSE MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE NEW AGENTS FOR NEUROBLASTOMA THERAPY NATIONAL COORDINATING INVESTIGATOR NATIONAL CO-SPONSOR NO RESPONSE OVERALL SURVIVAL OVER THE COUNTER PNEUMOCYSTIS CARNI PNEUMONITIS PROGRESSSIVE DISEASE PROGRESSION FREE SURVIVAL PAIRED-LIKE HOMEOBOX2B PRINCIPAL INVESTIGATOR PATIENT INFORMATION SHEET PHARMACOKINETICS POPULATION-MODELLING ANALYSIS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME ORALLY PAEDIATRIC PRECLINICAL TESTING PROGRAM PARTIAL RESPONSE RESEARCH ETHICS COMMITTEE RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS RIBONUCLEIC ACID BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 15 of 157 BEACON-Neuroblastoma Trial Protocol RTKI RT-qPCR SAE SAR SCT SD SFOP SIOPEN SNP SPC SUSAR SWFI T TH TMA TMG TSC TTo TVD UAR UKCCSG ULN VTE VEGF VGPR WMA RECEPTOR TYROSINE KINASE INHIBITORS REVERSE TRANSCRIPTASE QUANTITATIVE POLYMERASE CHAIN REACTION SERIOUS ADVERSE EVENT SERIOUS ADVERSE REACTION STEM CELL TRANSPLANT STABLE DISEASE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN NEUROBLASTOMA GROUP SINGLE NUCLEOTIDE POLYMORPHISM SUMMARY OF PRODUCT CHARACTERISTICS SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION STERILE WATER FOR INJECTION TEMOZOLOMIDE ARM TYROSINE HYDROXYLASE TISSUE MICROARRAY TRIAL MANAGEMENT GROUP TRIAL STEERING COMMITTEE TEMOZOLOMIDE + TOPOTECAN ARM TOPOTECAN, VINCRISTINE & DOXORUBICIN UNEXPECTED ADVERSE REACTION UNITED KINGDOM CHILDREN’S CANCER STUDY GROUP UPPER LIMIT OF NORMAL VENOUS THROMBO-EMBOLISM VASCULAR ENDOTHELIAL GROWTH FACTOR VERY GOOD PARTIAL RESPONSE WORLD MEDICAL ASSOCIATION FORMULAE Mosteller formula: BSA (m²) = BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 16 of 157 BEACON-Neuroblastoma Trial Protocol Table of Contents Trial Synopsis ...................................................................................................................................... 12 Title .................................................................................................................................................... 12 Trial Design ........................................................................................................................................ 12 Objectives .......................................................................................................................................... 12 Outcome Measures............................................................................................................................ 12 Patient Population .............................................................................................................................. 13 Sample Size ....................................................................................................................................... 13 Trial Duration...................................................................................................................................... 13 Abbreviations ..................................................................................................................................... 14 1. Background and Rationale ............................................................................................................. 22 1.1 Background............................................................................................................................ 22 1.1.1 Background for the dinutuximab beta amendment............................................................ 28 1.2 Trial Rational.......................................................................................................................... 29 1.2.1 Justification for design ....................................................................................................... 29 1.2.2 Rationale for patient population ......................................................................................... 30 1.2.3 Benefit-risk assessment .................................................................................................... 31 1.2.4 Rationale for the selected backbone schedules: Temozolomide, irinotecan + temozolomide and temozolomide + topotecan .............................................................................. 31 1.2.5 Rationale for dosing schedule of bevacizumab................................................................. 32 1.2.6 Rationale for evaluating chemo-immunotherapy in the BEACON-Neuroblastoma Trial... 32 1.2.7 Rationale for dosing schedule of dinutuximab beta........................................................... 33 1.2.8 Rationale for the use of biomarker studies ........................................................................ 34 1.3 Relevance and future importance ......................................................................................... 35 2. Objectives and Outcome Measures ............................................................................................. 36 2.1 Objectives .............................................................................................................................. 36 2.2 Outcome Measures ............................................................................................................... 37 3. Trial Design ..................................................................................................................................... 37 3.1 Randomisation....................................................................................................................... 37 3.2 Duration of treatment............................................................................................................. 38 3.3 Frequency and duration of follow-up ..................................................................................... 38 4. Eligibility.......................................................................................................................................... 39 4.1 Lifestyle guidelines ................................................................................................................ 39 5. Schedule of activities..................................................................................................................... 39 6. Screening and Consent ................................................................................................................. 40 6.1 Informed Consent .................................................................................................................. 40 6.2 Screening............................................................................................................................... 41 7. Trial Entry........................................................................................................................................ 42 7.1 Procedure for online patient randomisation........................................................................... 42 7.2 Emergency Randomisation ................................................................................................... 42 8. Treatment Details ........................................................................................................................... 43 8.1 Definition of Investigational Medicinal Products (IMPs) ........................................................ 43 9. Bevacizumab randomisation......................................................................................................... 43 9.1 Eligibility criteria for the bevacizumab randomisation............................................................ 43 9.1.1 Inclusion criteria for the bevacizumab randomisation ....................................................... 43 9.1.2 Exclusion criteria for the bevacizumab randomisation ...................................................... 44 9.2 Schedule of activities for the bevacizumab randomisation ................................................... 45 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 17 of 157 BEACON-Neuroblastoma Trial Protocol 9.3 Trial Therapy (bevacizumab randomisation) ......................................................................... 49 9.3.1 Bevacizumab randomisation trial treatment ...................................................................... 49 9.4 Treatment Schedule..................................................................................................................... 51 9.4.1 Day 1 of Cycle 1 ................................................................................................................ 51 9.4.2 Day 1 of subsequent cycles............................................................................................... 51 9.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12) ........................................................ 52 9.4.4 End of Treatment ............................................................................................................... 52 9.4.5 Treatment Duration............................................................................................................ 52 9.5 Dose Modifications for the bevacizumab randomisation ....................................................... 53 9.5.1 Dose Modifications for AEs due to chemotherapy - for the bevacizumab randomisation. 56 9.5.2 Bevacizumab – Infusion-related Reaction/Infusional Site Extravasation Management Guidelines ...................................................................................................................................... 62 9.5.3 Bevacizumab - Treatment Delays ..................................................................................... 63 9.5.4 Bevacizumab - Discontinuation ........................................................................................ 64 9.5.5 Bevacizumab - Toxicity Management guidelines .............................................................. 65 9.6 Central Venous Access Device (CVAD)................................................................................ 67 10 Dinutuximab beta and topotecan randomisations...................................................................... 68 10.1 Eligibility for the dinutuximab beta randomisation ................................................................. 68 10.1.1 Inclusion criteria for the dinutuximab beta randomisation ............................................. 68 10.1.2 Exclusion criteria for the dinutuximab beta randomisation ............................................ 69 10.2 Schedule of events for the dinutuximab beta and topotecan randomisations....................... 70 10.3 Trial therapy (dinutuximab beta and topotecan randomisations) .......................................... 74 10.3.1 Dinutuximab beta and topotecan trial treatment................................................................ 75 10.4 Treatment Schedule .............................................................................................................. 76 10.4.1 Day 1 of Cycle 1 ............................................................................................................ 76 10.4.2 Day 1 of subsequent cycles........................................................................................... 76 10.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12 on chemotherapy only) ............... 77 10.4.4 End of Treatment ........................................................................................................... 77 10.4.5 Treatment Duration............................................................................................................ 78 10.4.6 Cross-over ......................................................................................................................... 78 10.5 Dose Modifications – dinutuximab beta and topotecan randomisations ............................... 79 10.5.1 Dose modifications for dinutuximab beta specific toxicities .......................................... 79 10.5.2 Dose modifications for haematological toxicity.............................................................. 81 10.5.3 Dose modifications for hepatic toxicity .......................................................................... 82 11 Treatment Compliance................................................................................................................... 84 12 Supportive Treatment .................................................................................................................... 84 12.1 Nausea and Vomiting ............................................................................................................ 84 12.2 Growth Factors ...................................................................................................................... 84 12.3 Fever and neutropenia .......................................................................................................... 84 12.4 Blood products....................................................................................................................... 84 12.5 Pneumocystis jirovecii pneumonia (PJP) prophylaxis ........................................................... 84 12.6 Management of side effects caused by non-selective NSAIDs as cyclooxygenase (COX) type I and II inhibitors ......................................................................................................................... 84 12.7 Supportive care during Dinutuximab beta infusion................................................................ 85 12.7.1 Pain Management.......................................................................................................... 85 12.7.2 Prevention of dinutuximab beta related infusion reactions............................................ 86 13 Concomitant Medication................................................................................................................ 87 14 Assessments .................................................................................................................................. 87 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 18 of 157 BEACON-Neuroblastoma Trial Protocol 14.1 Response assessment .......................................................................................................... 88 15 Biomarkers...................................................................................................................................... 88 15.1 Blood sampling safety ........................................................................................................... 88 15.2 MRI-derived functional imaging biomarkers of angiogenesis................................................ 90 15.3 Molecular monitoring mRNA.................................................................................................. 90 15.4 Neuroblastoma exploratory biomarker analyses ................................................................... 90 15.5 Sample Collection.................................................................................................................. 92 15.5.1 Peripheral blood samples .............................................................................................. 92 15.5.2 Bone Marrow Samples .................................................................................................. 92 15.5.3 Archival tumour samples ............................................................................................... 92 16 Patient Follow Up ........................................................................................................................... 93 16.1 Patient Withdrawal................................................................................................................. 93 17 Pharmaceutical Information .......................................................................................................... 94 17.1 Definition of Investigational Medicinal Product ...................................................................... 94 17.2 Bevacizumab ......................................................................................................................... 94 17.2.1 Bevacizumab - Drug Supply .......................................................................................... 94 17.2.2 Bevacizumab - Ordering ............................................................................................... 94 17.2.3 Bevacizumab - Formulation, Packaging and Labelling ................................................. 94 17.2.4 Bevacizumab - Preparation and Dispensing ................................................................. 95 17.2.5 Compatibility information ............................................................................................... 95 17.2.6 Bevacizumab - Administration ....................................................................................... 95 17.2.7 Bevacizumab – Accountability....................................................................................... 96 17.2.8 Bevacizumab - Destruction............................................................................................ 96 17.3 Cyclophosphamide ................................................................................................................ 96 17.4 Dinutuximab beta................................................................................................................... 96 17.5 Irinotecan ............................................................................................................................... 96 17.5.1 Irinotecan - Drug Supply ............................................................................................... 96 17.5.2 Irinotecan - Formulation, Packaging and Labelling ....................................................... 96 17.5.3 Irinotecan - Preparation and Dispensing ....................................................................... 97 17.5.4 Compatibility information ............................................................................................... 97 17.5.5 Irinotecan - Administration ............................................................................................. 97 17.6 Temozolomide ....................................................................................................................... 97 17.6.1 Temozolomide – Drug Supply ....................................................................................... 97 17.6.2 Temozolomide - Formulation, Packaging and Labelling ............................................... 97 17.6.3 Temozolomide - Administration ..................................................................................... 97 17.7 Topotecan.............................................................................................................................. 98 17.7.1 Topotecan - Drug Supply.............................................................................................. 98 17.7.2 Topotecan - Formulation, Packaging and Labelling ..................................................... 98 17.7.3 Topotecan - Preparation and Dispensing ..................................................................... 98 17.7.4 Topotecan - Compatibility information ........................................................................... 98 17.7.5 Topotecan - Administration........................................................................................... 99 18 Adverse Event Reporting .............................................................................................................. 99 18.1 Reporting Requirements........................................................................................................ 99 18.1.1 Adverse Events (AE) ..................................................................................................... 99 18.1.2 AESIs of Bevacizumab .................................................................................................. 99 18.1.3 Serious Adverse Advents (SAE).................................................................................... 99 18.1.4 Reporting period .......................................................................................................... 100 18.2 Reporting Procedure ........................................................................................................... 100 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 19 of 157 BEACON-Neuroblastoma Trial Protocol 18.2.1 Site............................................................................................................................... 100 18.2.2 Trial Office ................................................................................................................... 102 18.2.3 Reporting to the Competent Authority and main Research Ethics Committee ........... 102 18.2.4 Investigators ................................................................................................................ 102 18.2.5 Data Monitoring Committee ......................................................................................... 102 18.2.6 Manufacturer of Investigational Medicinal Product...................................................... 102 19 Data Handling and Record Keeping ........................................................................................... 103 19.1 Data Collection .................................................................................................................... 103 19.2 Archiving .............................................................................................................................. 103 20 Quality Management .................................................................................................................... 103 20.1 Site Set-up and Initiation ..................................................................................................... 103 20.2 On-site Monitoring ............................................................................................................... 104 20.3 Central Monitoring ............................................................................................................... 104 20.4 Audit and Inspection ............................................................................................................ 104 20.5 Notification of Serious Breaches ......................................................................................... 104 21 End of Trial Definition .................................................................................................................. 105 22 Statistical Considerations ........................................................................................................... 105 22.1 Trial Design.......................................................................................................................... 105 22.2 Definition of Outcome Measures ......................................................................................... 106 22.2.1 Primary ........................................................................................................................ 106 22.2.2 Secondary.................................................................................................................... 106 22.2.3 Exploratory/Tertiary ..................................................................................................... 106 22.3 Sample Size......................................................................................................................... 106 22.4 Interim and Main Analyses of Outcome Measures.............................................................. 108 22.4.1 Planned Interim Analyses ............................................................................................ 108 22.4.2 Main Analysis............................................................................................................... 108 22.5 Stopping Guidelines ............................................................................................................ 110 23 Trial Organisational Structure..................................................................................................... 110 23.1 Coordinating Sponsor .......................................................................................................... 110 23.2 Co-Sponsor Centres ........................................................................................................... 110 23.3 Relationship of trial committees........................................................................................... 112 23.4 Trial Management Group..................................................................................................... 112 23.5 Trial Steering Committee ..................................................................................................... 112 23.6 Data Monitoring Committee................................................................................................. 112 23.7 Finance ................................................................................................................................ 113 23.8 NIHR CRN Portfolio ............................................................................................................. 113 24 Ethical Considerations ................................................................................................................ 113 25 Confidentiality and Data Protection ........................................................................................... 114 26 Insurance and Indemnity ............................................................................................................. 115 27 Publication Policy ........................................................................................................................ 116 28 Reference List............................................................................................................................... 117 Appendix 1 – WMA Declaration of Helsinki .................................................................................... 124 Appendix 2 - Definition of Adverse Events ..................................................................................... 127 Appendix 3 - Common Toxicity Criteria Grading ........................................................................... 129 Appendix 4 – RECIST Criteria 1.1 .................................................................................................... 130 Appendix 5 – Tumor Response at Metastatic Soft Tissue and Bone Sites (Park et al. 2017) ... 133 Appendix 6 - CURIE & SIOPEN scoring methods for neuroblastoma ......................................... 134 Appendix 7 – Temozolomide Dosing............................................................................................... 136 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 20 of 157 BEACON-Neuroblastoma Trial Protocol Appendix 8 – Blood Pressure Levels by Age and Height Percentile for Children and Adolescents ....................................................................................................................................... 139 Appendix 9 – Height for Age Chart - Girls ...................................................................................... 144 Appendix 10 – Height for Age Chart - Boys.................................................................................... 149 Appendix 11 – Lansky and Karnofsky/ECOG Scales .................................................................... 154 Appendix 12 – Tanner Staging ......................................................................................................... 156 Appendix 13 – Clinical studies of anti-GD2 therapies in combination with chemotherapy ...... 157 LIST OF TABLES Table 1 - Second line chemotherapy regimens tested in phase II in relapsed or refractory neuroblastoma since 2000 ..........
Url: /Media/UHS-website-2019/Docs/PaediatricOncology/beacon-protocol-v8.0-07mar2023-signed.pdf

DH IVIg approved indications summary_May 2012

Description: Demand Management Poster Red Priority - High Short Term Long Term Blue Priority - Medium Short Term Grey Priority - Low Long Term Black Condition Alloimmune thrombocytopenia (foeto-maternal/neonatal)* Chronic inflammatory demyelinating polyradiculoneuropathy Guillain-Barr? syndrome Haemolytic disease of the newborn HSCT in primary immunodeficiencies Immune thrombocytopenic purpura (acute and persistent, excluding chronic*) Condition Acquired red cell aplasia Autoimmune congenital heart block Autoimmune haemolytic anaemia Autoimmune uveitis Coagulation factor inhibitors (alloantibodies and autoantibodies) Haemophagocytic syndrome Immunobullous diseases Inflammatory myopathies Multifocal motor neuropathy Immune-mediated disorders with limited evidence of immunoglobulin efficacy Acute disseminated encephalomyelitis (if high-dose steroids have failed) Autoimmune encephalitis (including NMDA and VGKC antibodies, among others) Catastrophic antiphospholipid syndrome Cerebral infarction with antiphospholipid antibodies Chronic ITP CNS vasculitis Complex regional pain syndrome Neuromyotonia Intractable childhood epilepsy Neuromyotonia Opsoclonus Myoclonus Post-exposure prophylaxis for viral or pathogenic infection if intramuscular injection is contraindicated, or treatment when hyper-immune immunoglobulins are unavailable Pyoderma gangrenosum Systemic juvenile idiopathic arthritis Systemic vasculitides and ANCA disorders Urticaria (severe, intractable) Presumed immune-mediated disorders with little or no evidence of efficacy Acquired red cell aplasia NOT due to parvovirus B19 Acute idiopathic dysautonomia Aplastic anaemia/pancytopenia Atopic dermatitis/eczema Autoimmune neutropenia Chronic facial pain Diabetic proximal neuropathy Haemolytic uraemic syndrome PANDAS Paraneoplastic disorders that are known not to be B- or T-cell mediated POEMS SLE without secondary immunocytopenias (including juvenile) Immunodeficiency secondary to paediatric HIV infection Autologous BMT Adrenoleukodystrophy Alzheimer's disease Amyotrophic lateral sclerosis Chronic fatigue syndrome Critical illness neuropathy Multiple sclerosis Rheumatoid arthritis Neonatal sepsis (prevention or treatment) Sepsis in the intensive care unit not related to specific toxins or C. difficile Asthma Graves' ophthalmopathy IVF failure Recurrent spontaneous pregnancy loss Kawasaki disease Paraprotein-associated demyelinating neuropathy (IgM, IgG or IgA) Primary immunodeficiencies Specific antibody deficiency Thymoma with immunodeficiency Toxic epidermal necrolysis, Stevens Johnson syndrome Myasthenia gravis (including Lambert-Eaton myasthenic syndrome) Necrotising (PVL-associated) staphylococcal sepsis Post-transfusion purpura Rasmussen syndrome Secondary antibody deficiency (any cause) Severe or recurrent Clostridium difficile colitis Staphylococcal or streptococcal toxic shock syndrome Stiff person syndrome Transplantation (solid organ) * Updated May 2012
Url: /Media/SUHTExtranet/TrustMedicinesFormulary/Forms/DH-IVIg-approved-indications-Summary-Poster-Feb-2106.pdf

Asthma Themed Call Application Development Support_

Description: Asthma Health Technology Calls (AUK/BLF/EPSRC/NIHR i4i) Application Expert Review Group Background In late October 2020, the NIHR i4I and EPSRC, in alliance with Asthma UK/British Lung Foundation Partnership have launched/are launching - Themed Calls for Asthma. The specific calls are: * EPSRC Asthma Health Technology Awards https://epsrc.ukri.org/funding/calls/asthma-health-technology/ * NIHR Product Development Awards https://www.nihr.ac.uk/explore-nihr/funding-programmes/invention-for-innovation.htm * NIHR Challenge Awards https://www.nihr.ac.uk/explore-nihr/funding-programmes/invention-for-innovation.htm Following a strong steer from the NIHR-TRC, The National Asthma Strategy Group (NASG) and Asthma UK/BLF, the asthma research community are advised to come together to produce a small quantity of collaborative, high quality applications to the calls. To try to maximise the chances of success for the upcoming call by supporting the development of high quality applications, the NASG will establish an Application Expert Review Group composed of experts in the field of asthma, additional expertise drawn from the NIHR Respiratory Translational Research Collaboration, patients with asthma, methodologists and experts in engineering and physical sciences. Scope of the Expert Review Group Submission of applications to this Group is recommended for (I) academic led, (II) multi-institutional consortium bids across several NIHR-BRCs, however submission to the expert review group is not a mandatory prerequisite to submission to the call. Single centre applications to the grant schemes are encouraged to use internal peer review mechanisms within their host institution and other support as necessary (e.g. NIHR Research Design Services). The expert review group will not consider these applications. Applications where an industry partner is the lead application are also not within the remit of the expert review group as other support mechanisms exist e.g. NIHR NOCRI. Aims of the Asthma Themed Call Expert Review Group The aims of the Expert Review Group are to: * Consider the scope of the proposed research and provide guidance if appropriate * Provide guidance on the proposed research question(s), ensuring the anticipated outcomes of the research are of importance to and will benefit people with Asthma * Provide guidance on study design and methodology, where requested * Consider recruitment of study participants and make recommendations where appropriate * Identify additional potential collaborators who could add value to an application * Identify industry partners (SMEs and multi-national companies) who could add value to individual bids * Where possible, ensure a coordinated portfolio of applications which avoids unnecessary duplication and cross-over of applications Remit of the Asthma Themed Call Application Development Group Representatives from the Application Development Group will initially triage expressions of interest (EOI) in order to understand whether national level support is indicated and identify what type of support might be required. Expert Review Group (ERG) Individual Member Organisation Salman Siddiqui Chair, National Asthma Strategy Group Louise Brown Clinical trials methodologist, MRC Clinical Trials Unit, UCL Hitasha Rupani Asthma Expert, member of NASG, University Hospitals of Portsmouth NHS Trust Sejal Saglani Asthma Expert, member of NASG, Imperial College Ferhana Hashem Centre for Health Services Studies, University of Kent Name TBC Engineering and physical sciences expert member Name TBC Engineering and physical sciences expert member Alison Long Patient representative Name TBC Parent of a child with asthma Industry Collaboration support at the request of the ERG Samantha Walker & Krisnah Poinasamy Asthma UK/BLF partnership Ivana Poparic NIHR NOCRI The following individuals will be members of the Application Development Group responsible for the triage of applications. They will have responsibility for coordinating structured peer review and support tailored to specific applications. Nour Merzouki, NIHR R-TRC Operations Manager, Kate Holmes, Head of Collaborations NOCRI, will also be invited to join these meetings. Conflicts of Interest Expert review group (ERG) members will not be permitted to review applications if they are lead, co-applicant or named collaborator on any of the proposed themed calls. Members will be permitted to review applications that involve their host institution but will not be assigned as lead ERG member for these applications and submitters will be notified of the potential conflict of interest once the application has been reviewed. Asthma UK/BLF & NIHR will not participate in ERG peer reviews, however they will support the identification and pairing of industry collaborations that may enhance the core application at the request of the ERG. Timelines & Next Steps Potential academic applicants for the Asthma Themed calls will be invited to submit an expression of interest to the Application Development Group, via a centralised email address to Nour Merzouki (nour.merzouki@nihr.ac.uk ), from early November. Application deadlines for the various NIHR programmes have been announced/ will be announced at the time of the call launch and triage meetings for received applications will be scheduled as appropriate according to these deadlines (see below). Appendix 1: National Asthma Strategy Group NIHR R-TRC National Asthma Research Strategy Group The NIHR Respiratory Translational Research Collaboration (R-TRC) brings together internationally recognised investigators in the UK's leading centres of excellence to carry out multi-centre experimental and early phase research with industry, charities and other funders. The R-TRC has a renewed and refreshed strategy since 2017 to move beyond industry-centric studies to large collaborative multi-centre research projects. To help deliver this, the TRC has created a number of nation-wide research strategy groups across a number of priority respiratory disease areas, such as Asthma. The National Asthma Research Strategy groups aim to: * To identify the key research priorities and/or barriers which would require a collaborative approach to overcome and accelerate research for the benefit of patients * Develop and help deliver multi-site translational research projects/ activities which cannot be performed by one centre * Work with external funders, including commercial organisations, specialist societies and charities, to identify appropriate funding opportunities that will enable the delivery of these priority research activities * Support the alignment of research activities across the UK’s research landscape order to maximise on existing or leveraged investments and add value to complementary initiatives Appendix 2: NIHR Themed Call for Asthma Development Group Academic Expression of Interest Form Investigator details: Principal Investigator: Host Institution: Co-Investigators (Name, Institution): Contact details: Signature: Date submitted to the Application Development Board: Planned submission date to programme: Proposal details: Project title: Study type: Translational research Phase 1 Phase 2 Phase 3 Phase 4 Other (please describe) Research type: Primary research Secondary research Evidence synthesis Clinical trial/ investigation Other (e.g. mixed methods) Approximate number of participants required (if applicable): Approximate number of UK recruitment centres (if applicable): Research Plan: a maximum of 2 pages addressing the key points below: * A clear demonstration of the need and importance of the research * A brief overview of existing literature (primary research) * An outline of the research question to be addressed, including aim(s) and objectives * A short summary of the proposed project/ study plan outlining the study design and methods. For trials: please list trial phase, primary outcomes, secondary outcomes (please list first 3), UK recruitment target, approximate no. of UK sites and the patient population (age, genotype etc.) * A clear description of team member roles and contribution * Consideration of appropriate and relevant involvement of representatives from the CF community (PPI) Application development details: Which programme do you wish to submit your proposal to? EPSRC Asthma Health Technology Assessment ☐ NIHR i4i Product Development Award ☐ NIHR i4i Challenge Grant ☐ Application deadline: What help would you like from the Application Development group/s (investigators can tick more than one box): Scope of Research ☐ Guidance on proposed research question ☐ Engagement with Asthma Experts ☐ Study design ☐ Recruitment ☐ Collaborators including SMEs and Industry ☐ Alignment with other national proposals ☐ Abbreviated protocol review ☐ Other (please describe below) ☐ Definitions (taken from NIHR definitions and glossary) Study Type: Phase 0: Human micro dosing studies involving a small number of subjects to gather preliminary data on a drug’s pharmacokinetics and pharmacodynamics. Phase I: A clinical trial to project the pharmacology of a medicinal product when administered to humans, where the sponsor and investigator have no knowledge of any evidence that the product has effects likely to be beneficial to the subjects of the trial. Phase II: Trials that test the treatment in larger number of people with a given disease or condition. They aim to find out how well the treatment works in larger numbers, identify common side effects, and refine the dose and length of treatment. Phase IIa: Exploratory (non-pivotal) project that has clinical efficacy, pharmacodynamics or biological activity as primary endpoint, conducted in patients. Phase IIb: Definite dose range finding project in patients with efficacy as primary endpoint. Pilot: Pilot studies are a smaller version of the main study used to test whether the components of the main study can all work together. It is focused on the processes of the main study, for example to ensure that recruitment, randomisation, treatment, and follow-up assessments all run smoothly. Feasibility: Feasibility Studies are pieces of research done before a main study in order to answer the question "Can this study be done?". They are used to estimate important parameters that are needed to design the main study. Other Study: Other project to investigate a novel intervention to compare interventions, including devices, screening and diagnostics studies. This should not include phase III or IV trials. Research Type: Primary research: Experimental studies generating new data (cf. secondary research, which analyses existing data). Secondary research: A review of individual, existing (primary research) studies. A systematic review is a secondary study. Evidence synthesis: Evidence synthesis involves the development of techniques to combine multiple sources of quantitative and qualitative data to derive best evidence for use in healthcare.
Url: /Media/Southampton-Clinical-Research/Downloads/Asthma-Themed-Call-Application-Development-Support-.docx

ImmunoCOVID19 info for parents or carers and children aged 16-17

Description: Participant Information for parents/carers and children aged 16-17 years Study Title: Coronavirus infection in primary or secondary immunosuppressed children. Chief Investigator: H. de Graaf Principal investigators: H. de Graaf and S. N. Faust Paediatric clinical teams involved: Rheumatology, Immunology and Infectious Diseases, Gastroenterology, Renal, Respiratory, Oncology, Neonatology, General Paediatrics Hospitals involved: Multiple Hospitals across the UK Sponsor ID: RHM CHI1061 IRAS ID: 281544 Information sheet – adults and young persons aged 16-17 years Version: 1.7 Date: 22/03/2020 Website page: Dear parent/carer and young person, It is important to remember that if your child is unwell and needs medical care, you should follow the usual NHS clinical pathways. Thank you for considering participating in this online study, in which we aim to monitor children and young people who have a condition that make them more vulnerable to infections or are taking medication that affects their immune system during this coronavirus epidemic. It is important to stress that the information currently available from the most severely affected countries suggests that these conditions and drugs do not seem to affect the response to coronavirus in children. However, we (and many of our families who have contacted us already) think it is sensible to collect data about what happens to children with immune problems. This will then enable us to give you more informed advice. You and your child/young person are being invited to take part in this study. To help your family decide whether you would like your child to take part or not, it is important that you understand why the study is being done and what it will involve. Please read the information below carefully and ask questions if anything is not clear or you would like more information before you decide. If you need more information please discuss this with the consultant who takes care of your child or contact the study team. What is the study about? Some children are immunosuppressed or are being treated with drugs that affect their immunesystem. Most of these conditions and drugs have little effect on response to viral infections, and no serious coronavirus infections have been seen in immunosuppressed children so far from information currently available. However, as COVID-19 (the new coronavirus) is a new virus there is [22.03.2020] [Version number 1.7] CHI1061] [Ethics/IRAS number: 281544][Sponsor ID: RHM Information sheet over 16 yrs - Coronavirus infection in primary or secondary immunosuppressed children no information yet about how children with immune problems or on immune-suppressant drugs will respond. A coronavirus epidemic is likely not going to be prevented in the UK and many parents are worried about the risk this may pose to their children and to their family as a whole. We would like to keep a close eye on the children with conditions that make them more vulnerable to infections and those who are taking drugs that affect their immune response. If we collect information from as many patients as possible, we can then give more accurate advice. This study will send you a weekly online questionnaire. We aim to collect information to see whether more children with immune problems are getting the coronavirus infection and how it affects them. We can then use this information to advise parents during a weekly update. There is currently a national study looking at all people (adults and children) admitted to hospital with severe coronavirus infection. This is a separate study which you will be asked to take part in if your child/young person is admitted to hospital. We will share regular anonymised information and data (the study results) with colleagues across the UK and Europe, the NHS, Public Health England and the Department of Health. Information will be provided to parents from your regular clinical team in an easy to understand format as it becomes available. Why have I and my child/young person been asked to participate and what will happen if I and my child/young person takes part? If you or your child is less than 18 years old and has a condition that make them more vulnerable to infections or is on drugs that affect the immune system, you and your child have been asked to take part in this study. If you decide to take part, you will be asked to sign an informed consent on the next page of this website. After that there will be a short questionnaire about you or your child’s condition, the medication he/she is on and how you want to be contacted. After that you will be asked to fill in a weekly online questionnaire asking questions about possible symptoms of coronavirus infection, time off school and use of medication. Links to the up to date national information and advice will be given to you with every questionnaire. If you cannot answer any questions please just leave them blank, but if possible, please provide as much information requested as possible. We will send you the same questionnaire weekly until disease activity in the UK lessens, or you notify us you do not wish to take part. There will be an option to state “no symptoms” at the start of each questionnaire. After that we will put a summary of the results on this website. Participants will take part in the study for a maximum time of 1 year. Are there any benefits to my child taking part and are there any risks? There are no monetary (financial) benefits to taking part. The study may help the consultants caring for your child’s condition and teams all over the UK and Europe to know how to better look after children like yours. The NHS, Public Health England and Dept of Health and Social Care will be kept informed of ongoing results. If any new information arises during this study which would change our advice to children with immune system problems then Public Health England and the local services will be informed in order to adjust local guidance. On the other hand, if no risk factors are found after substantial data-collection, the data collected might be reassuring to parents and their children. There is no risk of taking part in this study. [22.03.2020] [Version number 1.7] CHI1061] [Ethics/IRAS number: 281544][Sponsor ID: RHM Information sheet over 16 yrs - Coronavirus infection in primary or secondary immunosuppressed children What data will be collected, will our data be kept confidential and will the NHS be given the result as soon as possible? Personal identification will be collected but will be anonymised in all analysis and only visible by the study team at University Hospital Southampton. The clinical consultants at your participating hospital (ie your clinic) will also have access to relevant local data. Your child’s participation and the information we collect about you and your child from the questionnaire will be kept strictly confidential. Your mobile number and email address are required to send you the link to the questionnaire. Your child’s date of birth, and details about their condition and their medications will be collected. If anything worrying is noted on a questionnaire the study team will liaise with the consultant who is caring for your child’s condition to inform them. However, it is important to remember that if your child is unwell and needs medical care you should follow the usual NHS clinical pathways. The weblinks to Public Health England regional and national advice will be available on the front page of the study website when a questionnaire link is opened in case you need them urgently (or dial NHS 111). Only members of the research team and responsible members of the University Hospital Southampton R&D team or your participating Trust R&D team may be given access to data about you for monitoring purposes and/or to carry out an audit of the study to ensure that the research complies with applicable regulations. Individuals from regulatory authorities (people who check that we are carrying out the study correctly) may require access to your data. All of these people have a duty to keep your child’s information, as a research participant, strictly confidential. This will ensure no data is traced back to your child following survey completion. Do you and your child have to take part? No, it is your decision whether you and your child/teenager may take part. What happens if I change my mind? You have the right to change your mind and withdraw at any time without giving a reason and without your child’s routine care being affected. If you want your information to be removed from the study, we will do that if possible, otherwise the information you have given will be included in the final analysis. Once data has been anonymised for analysis it will no longer be possible to identify it and withdraw it from the study. Where can I get more information? If you have any questions please ask your clinical consultant, all of whom know about this study if you have been sent this questionnaire. If you would like to get information in writing please contact the NIHR Clinical Research Facility in Southampton: Email: uhs.recruitmentCRF@nhs.net Telephone number: 023 8120 3853 If you have further questions please contact the Chief Investigator Dr. Hans de Graaf Email: immunoCOVID19study@uhs.nhs.uk [22.03.2020] [Version number 1.7] CHI1061] [Ethics/IRAS number: 281544][Sponsor ID: RHM Information sheet over 16 yrs - Coronavirus infection in primary or secondary immunosuppressed children What happens if there is a problem? If you wish to complain may wish to contact: PALS: 023 8120 6325 or patientsupportservices@uhs.nhs.uk Who has reviewed the study? The Leeds Research Ethics Committee has reviewed the study. Data Protection Privacy Notice The University Hospital Southampton conducts research to the highest standards of research integrity. When you agree to take part in a research study, we will use information about you in the ways needed, and for the purposes specified, to conduct and complete the research project. Under data protection law, ‘Personal data’ means any information that relates to and is capable of identifying a living individual. Personal data will be collected in this study. Only health related information will be collected as specified above. Please ask the research team if you have any questions or are unclear what data is being collected about your child. Thank you for taking the time to read this information booklet [22.03.2020] [Version number 1.7] CHI1061] [Ethics/IRAS number: 281544][Sponsor ID: RHM Information sheet over 16 yrs - Coronavirus infection in primary or secondary immunosuppressed children
Url: /Media/Southampton-Clinical-Research/Downloads/Immunocovid/ImmunoCOVID19-info-for-parents-or-carers-and-children-aged-16-17.pdf

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