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Study Synopsis Scientific title of clinical study A multi-centre, randomised, double blind, placebo-controlled trial evaluating the effects of early administration of fibrinogen concentrate in adults with major traumatic haemorrhage Public title of clinical study A randomised controlled trial to evaluate fibrinogen concentrate for severe bleeding after injury Early fibrinogen in major haemorrhage (E-FIT 1) Protocol Short Title/Acronym Protocol Version and Date Sponsor Funder Version 1.0 08/09/2015 NHSBT CSL Behring Feasibility trial Multi-centre, interventional, randomised, double-blind, parallel, placebo controlled trial Patients will be randomised 1:1 via pre-labelled study drug packs in ED The study will be run and conducted in UK Study design Health Condition(s) or Problem(s) Studied Key inclusion and exclusion criteria Major traumatic haemorrhage Inclusion criteria: Patients are eligible for this trial if: 1. Consent/assent is obtained (including waiver) 2. The participant is judged to be an adult (age 16 years or over) and is affected by traumatic injury 3. The participant is deemed by the attending clinician to have on-going haemorrhagic shock AND REQUIRES 4. Activation of the local major haemorrhage protocol for management of severe blood loss and/or transfusion of emergency (Group O) red cells Exclusion criteria: A patient will not be eligible for this study if he/she fulfils one or more of the following criteria: 1. 2. 3. 4. 5. The patient has been transferred from another hospital The trauma leader deems the injury incompatible with life More than 3 hours have elapsed from the time of injury Pregnant women Severe isolated TBI or unsalvageable head injury Setting Interventions to be compared Emergency Departments of participating hospitals Intervention arm: Early single intravenous infusion of trial drug (6g fibrinogen concentrate), within 45 minutes of admission to hospital, administered as a slow bolus over 5 minutes. Comparator arm: Early single intravenous infusion of placebo, within 45 minutes of admission to hospital, administered as a slow bolus over 5 minutes. Study hypothesis Primary outcome measure(s) Major bleeding after injury is exacerbated by a clotting abnormality acute traumatic coagulopathy (ATC). ATC is characterised by hypofibrinogenaemia and fibrinolysis. Early replacement of fibrinogen will treat the coagulopathy and may reduce bleeding and improve outcomes. This study will evaluate the clinical and laboratory effects of early fibrinogen supplementation during major traumatic haemorrhage. (n = 40): 1. Feasibility of administering FgC within 45 minutes of admission. 2. Proportion of patients with at least one Clauss fibrinogen level 2 g/L during active haemorrhage. Key Secondary outcome measure (s) 1. Transfusion volumes, in numbers of units, for red cells, plasma, platelets and cryoprecipitate at 3, 6 hours and 24 hours from admission 2. Clauss fibrinogen levels at day 7 post randomisation 3. ROTEM measures of coagulation (EXTEM and FIBTEM, where available) to day 7 post randomisation 4. Thrombotic events: venous thromboembolism (DVT, PE) and arterial events (MI, stroke) to day 28 from randomisation 5. Duration of and/or requirement for organ support to day 28 from admission, as defined by the CTCOFR score 6. All-cause mortality (including death from bleeding) at 3, 6 and 24 hours and up to day 28 from admission. Mortality at 1 year by longer term follow up 7. Hospital stay including ICU/HDU stay 8. Quality of life 9. Proportion of patients achieving haemostasis at 3 hours from admission (defined using a trial specific haemorrhage assessment tool) Duration of Study Duration of set up 6 months to obtain all ethical/regulatory approvals, finalise contracts, prepare essential documents and study database and initiate study centres. Duration of recruitment The trial will recruit over 18 months, based on an average recruitment rate of 2.5 patients/month. Duration of follow-up for each participant will be 28 days. Duration of study close out 6 months to complete all data cleaning and statistical analysis and site close out. The planned total trial duration is 30 months. Countries of recruitment Target Sample Size UK 24 patients per arm, 48 patients in total, to allow an extra 20% for drop out Date of first enrolment Anticipated date of enrolment of the first participant will be December 2015 Ancillary Studies/sub-studies Fibrinogen is a key coagulation protein, without which stable clots cannot be formed. Recent advances in scientific evaluation of clot formation have meant that it is possible to evaluate the effects of treatments using a microfluidic environment. This ancillary study will evaluate the effect of FgC on the formation of clots under shear stress in a microfluidic system. This will enable the comparison of patients in receipt of FgC with those who do not receive early fibrinogen supplementation. This study will be conducted only at centres with sufficient laboratory haemostasis expertise. As many as 4 in every 10 patients affected by severe trauma die from uncontrolled bleeding. Many of these patients are found to have an abnormality of the clotting system, known as acute traumatic coagulopathy (ATC). The two most important abnormalities in ATC are a low fibrinogen and increased clot breakdown. It has been hypothesised, and there are some nonrandomised studies that show, that treatment of trauma patients who are bleeding with fibrinogen therapy stops bleeding more effectively than standard care, reduces transfusion needs and may reduce death rates. This study will look at the effects of infusing a drug (fibrinogen concentrate) which is a concentrated source of fibrinogen, to adult trauma patients within 45 minutes of admission to hospital. It has been shown from a large trauma RCT that early treatment for bleeding has better outcomes. This study will evaluate whether it is possible to infuse drug within 45 minutes and will also look at laboratory and clinical outcome measures. Lay Summary of Study