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

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).