{"id":"14/190/01","award_type":"Research","award_title":"The CRASH-3 Trial: Tranexamic acid for the treatment of significant traumatic brain injury","award_amount":1204148.8,"award_amount_disp":"1,204,148.76","app_abstract":"There are more deaths each year from injuries than from HIV, TB and malaria combined. Worldwide, about ten million people are killed or hospitalised because of a head injury every year. Most head injuries are caused by road traffic crashes, and because car use is increasing, the number of people suffering a head injury is increasing.     Amongst those who survive a head injury, many are left severely disabled for the rest of their lives. For example, there is a high likelihood that Michael Schumacher will be permanently disabled as a result of his recent head injury. Most victims of head injury are young adults living in low and middle income countries. Because many of the victims are also breadwinners for their families, head injuries can also result in loss of income which, along with medical costs, can increase household debt and lead to a fall in living standards for the whole family.     When the head is injured there is often bleeding inside the brain, which can continue for some time and worsen after hospital admission. This bleeding increases pressure inside the skull causing further damage to the brain, which can be fatal or result in serious disability for the patient. We think that we can prevent some of these deaths and disability by reducing the amount of bleeding in the brain after head injury.     Tranexamic acid is a cheap drug that reduces bleeding in other conditions. A large trial in accident victims (other than those with head injury) found that it reduces the chances of bleeding to death. If this drug also works in patients with head injury and bleeding into the brain, this would be important to know because it could save lives at a very low cost. We have already done two preparatory studies to see if tranexamic acid can help people who have bleeding inside the brain because of a head injury. Together, the results of the studies suggest that tranexamic acid should reduce the amount of bleeding inside the brain and could reduce their chances of dying or being disabled. However, because these studies were small, we are not very certain about the accuracy of their results. Also, they were not designed to find out whether tranexamic acid reduces disability.     Because doctors are still unsure about whether tranexamic acid works, it is not given to patients with traumatic brain injury. But if a new clinical trial showed that it worked, this would change very quickly. We want to find out if tranexamic acid saves lives and reduces disability in people with traumatic brain injury. We plan to study 10,000 patients with traumatic brain injury in countries throughout the world. We will give half of them tranexamic acid and the other half a dummy medicine called a placebo. To make sure that the two groups are the same apart from tranexamic acid, we will decide who gets tranexamic acid and who gets placebo using the modern equivalent of the toss of a coin (this is called randomisation). Everyone will of course get all the treatments that doctors usually give to traumatically brain injured patients. At the end of the trial we will see if giving tranexamic acid on top of all the usual treatments improves survival and other patient outcomes.     The study will be carried out by a team of researchers with lots of experience in doing clinical trials. In fact, it will be the same team that did the successful study of tranexamic acid in accident victims. The trial will cost several million pounds but if it shows (as we hope it will) that tranexamic acid works, we will have a very cheap way of reducing the number of people who die and are disabled after a head injury. The start-up phase of trial is underway and over a thousand patients have been recruited. The trial procedures work well. This application is for funds to continue recruitment to 10,000 patients.","app_plain_english_summary":"Worldwide, over 10 million people are killed or hospitalised because of traumatic brain injury (TBI) each year. Approximately 90% of deaths from TBI occur in low and middle income countries. TBI predominantly affects young adults and many patients experience long lasting or permanent disability. The social and economic burden of TBI is considerable. With rapidly increasing motorisation, the incidence of TBI is predicted to rise in low and middle income countries. An effective, widely practicable and affordable treatment for TBI could save many thousands of lives and substantially reduce the burden of disability.     The antifibrinolytic agent tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. A systematic review of randomised trials of TXA in elective surgical patients shows that TXA reduces the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding.4 These differences are all highly statistically significant. Furthermore, there is no evidence of any increased risk of vascular occlusive events with TXA.    More recently, TXA has been shown to reduce mortality in trauma patients with significant extra cranial bleeding. The CRASH-2 trial, which enrolled 20,211 bleeding trauma patients from hospitals in 40 countries, showed that the administration of TXA within 8 hours of injury significantly reduces deaths due to bleeding (RR=0.85, 95% CI 0.76 0.96; p=0.008), and all-cause mortality (RR=0.91, 95% CI 0.85 0.97; p=0.0035) compared to placebo, with no apparent increase in vascular occlusive events. Among patients treated very soon after injury, the reduction in mortality with TXA is even greater. Cost-effectiveness analysis has shown that the administration of TXA to bleeding trauma patients is highly cost effective in low, middle and high income settings. As a consequence of the CRASH-2 trial results, TXA has been incorporated into trauma treatment protocols worldwide and has been included on the WHO List of Essential Medicines.     The knowledge that TXA reduces blood loss in surgery and reduces mortality in traumatic bleeding raises the possibility that it might also be effective in TBI. Intracranial haemorrhage is common after TBI and is associated with increased mortality and disability. In the MRC CRASH-1 trial, which included 10,008 TBI patients, 73% of patients with moderate or severe TBI had intracranial haemorrhage on CT scan. Haemorrhage size is strongly associated with outcome. Patients with a large intracranial haemorrhage, whatever the location, have a substantially higher mortality than patients with a small haemorrhage. In many TBI patients, the intracranial bleeding continues after hospital admission. Among patients with moderate or severe TBI, who are found to have intracranial bleeding on a CT scan taken soon after hospital admission, intracranial bleeding progresses in 84% of patients.     Approximately one third of patients with TBI have laboratory evidence of abnormal coagulation at hospital admission. These patients have an increased risk of intracranial haemorrhage and higher mortality. Increased fibrinolysis, as indicated by high levels of fibrinogen degradation products, is common in TBI and is a strong independent predictor of progressive intracranial haemorrhage. These observations raise the possibility that TXA might reduce intracranial haemorrhage and improve patient outcomes in TBI patients.     In addition, it has been shown that progressive tissue damage and oedema develops in regions surrounding intracranial bleeding lesions, and is associated with worse outcome. Tissue plasminogen activator (tPA) has been shown to be an important factor in this process of peri-lesional oedema. By blocking the conversion from plasminogen to plasmin, TXA counteracts the effect of tPA and therefore, it is possible that TXA mi","headline":"Tranexamic acid was safe in patients with traumatic brain injury and treatment within 3 hours of injury reduced head injury-related death, with a cost/QALY of £4300 in those with mild or moderate head injury.","hrcs_health_category":["Injuries and Accidents"],"rac_code":["6.1 Pharmaceuticals"],"research_type":"Primary Research","programme":"Health Technology Assessment","funding_stream":"HTA Clinical Trials & Evaluation","award_status":"Completed","programme_stream":"Researcher Led","contracting_org":"London School of Hygiene & Tropical Medicine","centre":"NETSCC","contracting_org_title":"Contracting Organisation","start_date":"2014-10-01T23:59:59.000+0000","end_date":"2020-01-31T23:59:59.000+0000","pub_date":"2021-04-30T23:59:59.000+0000","lead_investigator_title":"Chief Investigator","lead_investigator_name":["Professor Ian Roberts"],"lead_investigator_orcid":["0000-0003-1596-6054"],"co_investigator_name":["Dr Katharine Ker","Professor Adeniran Fawole","Professor Antonio Belli","Professor Haleema Shakur-Still","Professor Matthew Shokunbi","Professor Rashid Jooma","Professor Rizwana Chaudhri","Professor Tim Harris"],"co_investigator_orcid":["0000-0002-1514-5005","","0000-0002-3211-9933","0000-0002-6511-109X","0000-0002-7819-6862","0000-0001-6627-3245","0000-0002-5428-3988","0000-0002-9146-258X"],"research_call":"CRASH 3 : Tranexamic acid trial MRC / HTA joint fund 2014","call_id":"14/190","link_type":["Clinical Trials Registry"],"link_title":["ISRCTN Registry"],"link_URL":["http://www.isrctn.com/ISRCTN15088122"],"link_group":["Overview"],"link_date_year":[0],"link_date":["1900-01-01T23:59:59.000+0000"],"award_website":"https://crash3.lshtm.ac.uk/","funder":"NIHR (non-ODA)","reg_number_title":["ISRCTN"],"reg_number":["15088122"],"reg_number_url":["http://www.isrctn.com/ISRCTN15088122"],"additional_funder":"","jl_rep_id":"https://doi.org/10.3310/hta25260","jl_rep_title":"Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT","jl_rep_pub_date":"2021-04-30T23:59:59.000+0000","doc_type":["Protocol","Protocol","STUDm","STUDm"],"doc_group":["Methods","Methods","Methods","Methods"],"doc_title":["Protocol","Protocol","Study Documentation","Study Documentation"],"doc_URL":["https://njl-admin.nihr.ac.uk/document/download/2024883","https://njl-admin.nihr.ac.uk/document/download/2026455","https://njl-admin.nihr.ac.uk/document/download/2033524","https://njl-admin.nihr.ac.uk/document/download/2033542"],"doc_date":["2016-11-10T23:59:59.000+0000","2016-11-10T23:59:59.000+0000","2020-04-24T23:59:59.000+0000","2020-04-24T23:59:59.000+0000"],"doc_date_year":[2016,2016,2020,2020],"doc_ver":["V20","V20","V02","V01"],"output_type":["Journal Article","Journal Article"],"output_title":["Cost-effectiveness analysis of tranexamic acid for the treatment of traumatic brain injury, based on the results of the CRASH-3 randomised trial: a decision modelling approach","Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial"],"output_authors":["Williams J, Roberts I, Shakur-Still, Lecky F, Chaudhri, R, Miners A","The CRASH-3 trial collaborators"],"output_url":["https://gh.bmj.com/content/5/9/e002716","https://doi.org/10.1016/S0140-6736(19)32233-0"],"output_date":["2020-09-02T23:59:59.000+0000","2019-10-14T23:59:59.000+0000"],"output_date_year":[2020,2019],"output_journal":["BMJ Global Health","Lancet The"],"output_group":["Results","Results"],"highlighting":"","full_contracting_org":"London School of Hygiene & Tropical Medicine","_version_":1875670578026774528,"full_co_investigator_name":["Dr Katharine Ker","Professor Adeniran Fawole","Professor Antonio Belli","Professor Haleema Shakur-Still","Professor Matthew Shokunbi","Professor Rashid Jooma","Professor Rizwana Chaudhri","Professor Tim Harris"],"start_year":2014,"full_lead_investigator_name":["Professor Ian Roberts"]}