The CRYOSTAT2 trial: The rationale and study protocol for 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 activation

Curry, Nicola; Davenport, Ross; Lucas, Joanne; Deary, Alison; Benger, Jonathan; Edwards, Antoinette; Evans, Amy; Foley, Claire; Green, Laura; Morris, Stephen; Thomas, Helen; Brohi, Karim; Stanworth, Simon J

Abstract

Objectives: To describe the protocol for a multinational randomised, parallel, superiority trial, in which patients were randomised to receive early high-dose cryoprecipitate in addition to standard major haemorrhage protocol (MHP), or Standard MHP alone. Background: Blood transfusion support for trauma-related major bleeding includes red cells, plasma and platelets. The role of concentrated sources of fibrinogen is less clear and has not been evaluated in large clinical trials. Fibrinogen is a key pro-coagulant factor that is essential for stable clot formation. A pilot trial had demonstrated that it was feasible to deliver cryoprecipitate as a source of fibrinogen within 90 min of admission. Methods: Randomisation was via opaque sealed envelopes held securely in participating Emergency Departments or transfusion laboratories. Early cryoprecipitate, provided as 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g fibrinogen supplementation), was transfused as rapidly as possible, and started within 90 min of admission. Participants in both arms received standard treatment defined in the receiving hospital MHP. The primary outcome measure was all-cause mortality at 28 days. Symptomatic thrombotic events including venous thromboembolism and arterial thrombotic events (myocardial infarction, stroke) were collected from randomisation up to day 28 or discharge from hospital. EQ5D-5Land Glasgow Outcome Score were completed at discharge and 6 months. All analyses will be performed on an intention to treat basis, with per protocol sensitivity analysis. Results: The trial opened for recruitment in June 2017 and the final patient completed follow-up in May 2022. Discussion: This trial will provide firmer evidence to evaluate the effectiveness and cost-effectiveness of early high-dose cryoprecipitate alongside the standard MHP in major traumatic haemorrhage.

• Journal Article Type: Article
• Acceptance Date: Oct 3, 2022
• Online Publication Date: Nov 2, 2022
• Deposit Date: Dec 20, 2022
• Journal: Transfusion Medicine
• Print ISSN: 1365-3148
• Electronic ISSN: 1365-3148
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1111/tme.12932
• Keywords: trauma, Haemorrhage, cryoprecipitate, fibrinogen, transfusion
• Public URL: https://uwe-repository.worktribe.com/output/10148256
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1111/tme.12932
• Additional Information: This study was prospectively registered on Current Controlled Trials on 24/04/2017 (ISRCTN: ISRCTN14998314), and is also registered on Clinicaltrials.gov ID: (NCT04704869). The study was approved by the South Central—Oxford C Research Ethics Committee (17/SC/0164 26/05/2017) and by the Confidentiality Advisory Group (19/CAG/0161 28/01/2020).; ; Data availability statement:; The full protocol is publicly available on the study website (https://cryostat2.co.uk/downloads/trial-protocol.pdf). The current protocol version is 4.0 dated 15/02/2022. The participant-level dataset after de-identification will be available via the Chief Investigator upon reasonable request and review by the research team. The statistical analysis plan is available from the Lead Statistician upon reasonable request.