Award Title: CRYOSTAT-2: A multi-centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol (MHP) activation
Funder: Department of Health and Social Care

Abstract: Every year in the UK, trauma (e.g. car accidents, stabbings) kills 12,500 people, with most of those who die under the age of 45.  For the same age group that is more than cancer, HIV/AIDS and heart disease combined. One of the most common causes of death in trauma patients is uncontrolled bleeding. At present, standard treatment for severe bleeding involves rapid infusion of red blood cells and blood components e.g. plasma and platelets in large volumes. Until recently one out of every two people who received a massive blood transfusion (more than 10 pints) would die from their injuries.  Two important studies involving bleeding trauma patients have been conducted in the last five years showing that early intervention is more effective after injury and may help save lives._x000D_
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Patients who have severe bleeding after injury develop a problem with their clotting system which means that they tend to bleed more. One of the main problems is due to low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ which holds a blood clot together and at low levels, blood clots don’t form properly and bleeding can continue. Cryoprecipitate is a frozen blood component prepared from plasma and rich in fibrinogen. By transfusing cryoprecipitate early to replace fibrinogen levels in bleeding trauma patients) we believe blood clots will be more stable and reduce bleeding.. We hope that this new approach will in turn save lives. _x000D_
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We propose to undertake a large research study, called a randomised controlled trial where patients are randomly divided into two groups and treatments are compared: A) standard treatment with normal blood transfusions B) early cryoprecipitate + standard treatment with normal blood transfusions, to see if cryoprecipitate can improve survival in trauma patients with severe bleeding.  We are using cryoprecipitate because it contains high levels of fibrinogen, has been used across the UK since the 1960’s and is considered a safe way of increasing a patient’s fibrinogen levels. _x000D_
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In UK hospitals, results from a large study across 22 centres show that cryoprecipitate is given on average three hours after injury. We think this is too late and want to give a high dose of cryoprecipitate within 90 minutes of a bleeding trauma patient’s admission to hospital. _x000D_
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The majority of patients entered into this clinical trial will be too unwell to agree to participate in the study. Our intention is to use Professional Consultees (doctors who are independent from the research team) or Personal Consultees (relatives) to provide agreement for entering a patient into the study.  Patients will then be asked to provide consent to remain in the study when their condition has improved. We have consulted several Patient and Public Involvement groups who understand the need for this method of consent and support this process._x000D_
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This study will determine whether or not giving cryoprecipitate treatment reduces death rates. Trauma patients with severe bleeding who are taken to any Major Trauma Centre across the country with be eligible to enter the trial. The Major Trauma Network in England and NHS Blood and Transplant will support the delivery of cryoprecipitate for this study.  The results of this study will have the potential to influence the way doctors and nurses all over the world treat trauma patients. We hope this innovative trial will contribute to the advancement of medicine and save many lives.

Lay Abstract: OBJECTIVE: Determine whether early high-dose fibrinogen supplementation with cryoprecipitate reduces mortality in adult trauma patients with haemorrhagic shock and active bleeding.  DESIGN: Multicentre, parallel group randomised controlled clinical trial.  SETTING: Major Trauma Centres in England (HTA) and international Level 1 trauma centres (matched funding from Bart’s Charity to support recruitment).  TARGET POPULATION: Adult patients suffering major trauma haemorrhage requiring activation of the local major haemorrhage protocol (MHP).  EXCLUSION CRITERIA:  Transferred from another hospital or injury is thought to be incompatible with life or more than 3 hours elapsed from time of injury.  HEALTH TECHNOLOGY BEING ASSESSED: Early cryoprecipitate (3 pools), equivalent to a dose of 6g fibrinogen, in addition to standard of care for resuscitation (MHP). Cryoprecipitate administration will start as soon as possible and within 90 minutes of admission.  MEASUREMENT OF COSTS AND OUTCOMES: Primary efficacy outcome is all-cause mortality at 28 days. Secondary efficacy outcomes include: all-cause mortality, & death from bleeding: at 6 and 24 hours and all-cause mortality at 6 months; transfusion requirements: red blood cells (RBC), platelets, fresh frozen plasma (FFP) and cryoprecipitate to 24 hours. Safety assessments include: evaluation of thrombotic events (clinically overt venous thromboembolism or arterial ischaemic event (myocardial infarction, stroke) up to day 28 or discharge from acute care facility.  We will evaluate the impact of early cryoprecipitate on Quality of Life (QoL) at discharge and six months following discharge using Glasgow Outcome Scale (GOS) and EQ5D-5L questionnaires.  Pre-defined subgroup analysis: mortality according to timing of cryoprecipitate administration. We have considerable experience of the data collection forms based on our feasibility trials, which will be further refined for pragmatic use.   SAMPLE SIZE: A total of 1544 patients will be needed, 772 in each treatment group, to detect difference of 7% in mortality (from 26% to 19%) as significant at the 5% significance level, with 90% power.   A pilot phase will include the 12 months from when the first patient is randomised. An interim analysis will be carried out after 300 patients have been recruited.  PROJECT TIMETABLE INCLUDING RECRUITMENT RATE: Data from the 22 MTCs in England show that MHPs are activated 75-150 times per year, equating to a potential population of at least 1,500 patients per year.  We require 25% of this cohort (375 patients per year, 1125 in total) taking into consideration a slower initial recruitment rate in the first six months whilst MTCs become active sites.  International recruitment is estimated at 140 patients per year (419 in total) across six Level 1 centres using same accrual rates as England although interested international centres in comparison to English sites have a higher frequency of MHP activation. The pragmatic trial protocol will ensure recruitment targets are met and completed within three years.  We believe the recruitment target is within the capacity of the national major trauma system and interested international trauma centres (see letters of support).

Research Activity Codes: 6.4 SURGERY
Health Categories: INJURIES AND ACCIDENTS