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Background Traumatic haemorrhage is common after severe injury, leading to disability and death. Cryoprecipitate, a source of fibrinogen, may improve outcomes for patients with traumatic haemorrhage. Objective To investigate the effects of early fibrinogen supplementation in the form of 3 pools (15 units, approximately 6 g of fibrinogen) of cryoprecipitate on 28-day mortality. Design A randomised, parallel-group, unblinded, multicentre, international trial and economic evaluation. Patients were randomised to either the intervention (early cryoprecipitate) or the comparator (standard major haemorrhage protocol) arm via opaque, sealed envelopes in the emergency department or the transfusion laboratory/blood bank. All analyses were performed on an intention-to-treat basis. A cost-effectiveness analysis was undertaken. Setting Twenty-five major trauma centres in the UK and one level 1 trauma centre in the USA. Participants Adults who had traumatic haemorrhage following severe injury requiring activation of the major haemorrhage protocol and had received a blood transfusion. Intervention Early cryoprecipitate – 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g of fibrinogen supplementation), infused as rapidly as possible, within 90 minutes of arrival at hospital in addition to standard major haemorrhage protocol or standard major haemorrhage protocol only. Main outcome measures The primary outcome was all-cause mortality at 28 days. The secondary outcomes were all-cause mortality at 6 hours, 24 hours, 6 months and 12 months from admission; death from bleeding at 6 hours and 24 hours; transfusion requirements at 24 hours from admission; destination of participant at discharge; quality-of-life measurements (EuroQol-5 Dimensions, five-level version and Glasgow Outcome Scale) at discharge/day 28 and 6 months after injury; and hospital resource use up to discharge or day 28 (including ventilator-days, hours spent in critical care and inpatient stays). Results Eight hundred and five patients were randomised to receive the standard major haemorrhage protocol (control arm). Seven hundred and ninety-nine patients were randomised to receive an additional three pools of cryoprecipitate in addition to standard care (intervention arm). Baseline characteristics appeared well matched. Patients had a median age of 39 (interquartile range 26–55) years, and the majority (79%) were male. All-cause 28-day mortality (n = 1531 patients; intention to treat) was 25.3% in the intervention arm compared with 26.1% in the control arm (odds ratio 0.96; p = 0.74). Limitations There was variability in the timing of cryoprecipitate administration, with overlap between the treatment arms, limiting the degree of intervention separation. Conclusions There was no evidence that early empiric administration of high-dose cryoprecipitate reduced the risk of death in unselected patients with traumatic haemorrhage. There was also no difference in adverse events. The cost-effectiveness of the intervention was similar to that of standard care. Future work Research to evaluate if fibrinogen replacement is more beneficial for selected patients, for example those with low fibrinogen blood levels, is needed, as is further exploration of whether there is a difference in outcome according to mechanism of injury. Trial registration This trial is registered as ISRCTN14998314. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/57/02) and is published in full in Health Technology Assessment; Vol. 28, No. 76. See the NIHR Funding and Awards website for further award information. Plain language summary Uncontrolled bleeding following injury is a leading cause of death and disability, killing over 12,000 people in the United Kingdom every year. People who have severe bleeding after injury often develop a problem with their clotting system that means that they tend to bleed more. One change after trauma is low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ that holds a blood clot together. At low levels, blood clots do not form properly, and bleeding can continue. Cryoprecipitate is stored as a frozen type of blood component that is prepared from plasma after blood donation. It is rich in fibrinogen. This study investigated whether giving a high dose of cryoprecipitate transfusion as soon as possible after injury reduced death rates. We studied people who required a blood transfusion following major injury due to trauma admitted at 26 hospitals in the United Kingdom and the United States of America. A total of 1604 people were allocated at random to one of two study groups. One group were given an early transfusion of high-dose cryoprecipitate in addition to standard treatments including other blood transfusions. The other group received the standard treatment alone. Outcomes from 1531 participants were analysed. Among participants treated with the additional early cryoprecipitate, the death rate was 25.3% (192/760). In the standard treatment group, the death rate was 26.1% (201/771). There was no evidence that treating patients with early high-dose cryoprecipitate had an effect on the death rate. There were also no differences in side effects. The economic analysis shows that, overall, treatment costs and quality of life did not differ between patients who received early cryoprecipitate and patients who did not. Scientific summary Background Worldwide, trauma accounts for 5.8 million deaths every year, equivalent to 1 death every 9 minutes, and is the leading cause of death in persons under the age of 44 years. Bleeding accounts for 40% of all injury-related deaths, many within hours of injury, and there is a high burden from major haemorrhage on both patients and the NHS. Twenty-five per cent of all trauma patients have abnormal blood clotting, which causes higher rates of bleeding, major haemorrhage and a three- to fourfold increase in the risk of death. There are two main clotting abnormalities: low fibrinogen levels (hypofibrinogenaemia) and increased clot breakdown (fibrinolysis). Cryoprecipitate is the current standard source of concentrated fibrinogen in the UK. Cryoprecipitate may improve outcomes for patients with traumatic haemorrhage by improving clot strength, reducing blood loss and, hence, increasing survival. This is supported by data from our pilot study (CRYOSTAT-1) that showed that the early replacement of fibrinogen with cryoprecipitate was able to rapidly restore fibrinogen levels and may reduce mortality rates from traumatic haemorrhage. Objectives We assessed the effects and cost-effectiveness of the early administration of high-dose cryoprecipitate to traumatic haemorrhage patients on death rates, transfusion requirements and adverse events. Methods The CRYOSTAT-2 trial was a randomised, parallel-group, unblinded, multicentre, international trial conducted in 25 major trauma centres in the UK and at one level 1 trauma centre in the USA. Adults who had traumatic haemorrhage following severe injury necessitating activation of the major haemorrhage protocol (MHP) and received a blood transfusion were eligible. (Standard MHPs in the UK include empiric cryoprecipitate in the second pack of blood components if a patient continues to bleed.) Patients were randomly allocated to receive early high-dose cryoprecipitate (3 pools, equivalent to 15 single units of cryoprecipitate or 6 g of fibrinogen supplementation) in addition to the standard MHP or the standard MHP only. Fibrinogen levels were not required at randomisation. The primary outcome was all-cause mortality at 28 days. The secondary outcomes were all-cause mortality at 6, 24 hours, 6 months and 12 months from admission; death from bleeding at 6 hours and 24 hours; transfusion requirements for red blood cells, platelets, fresh-frozen plasma and cryoprecipitate at 24 hours from admission; destination of participant at discharge; quality-of-life measurements (EuroQol-5 Dimensions, five-level version, and Glasgow Outcome Scale) at discharge/day 28 and 6 months after injury; and hospital resource use up to discharge or day 28 (including ventilator-days, hours spent in critical care and inpatient stays). We assessed the cost-effectiveness of the early administration of high-dose cryoprecipitate in addition to the standard MHP compared with that of standard MHP only. The original planned sample size was 1568 (later amended). Results Patients were allocated to early cryoprecipitate in addition to the MHP (n = 799) or to the MHP alone (n = 805). A total of 1604 patients were enrolled, of whom 1531 had outcome data available for analysis (intervention arm, n = 760; standard care arm, n = 771). Patients in both treatment arms were well matched on all baseline clinical characteristics, with a median age of 39 [interquartile range (IQR) 26–55] years; 79% were male. The median Injury Severity Score was 29 (IQR 18–43), consistent with major injury. Overall, any cryoprecipitate was administered within the first 24 hours of arrival at hospital to 85% of patients in the intervention arm and 32% of patients in the standard care arm. By intention-to-treat analysis, 25.3% died in the intervention arm compared with 26.1% in the standard care arm [odds ratio (OR) 0.96; p = 0.74]. Mortality was also similar between the treatment arms at 6 and 24 hours. There were no differences between the treatment arms in secondary outcomes, including 24-hour transfusion requirements (other than cryoprecipitate) and safety outcomes (thrombotic). Conclusions Our findings do not support empiric fibrinogen supplementation for all trauma patients suspected of bleeding. The study supports current MHP practices, whereby concentrated fibrinogen therapies such as cryoprecipitate are given often in the second ‘MHP pack’, or reactively in response to repeated monitoring for low fibrinogen concentrations. Trial registration This trial is registered as ISRCTN14998314. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/57/02) and is published in full in Health Technology Assessment; Vol. 28, No. 76. See the NIHR Funding and Awards website for further award information.