Efficacy of Pre-Hospital Administration of Fibrinogen Concentrate (Clottafact®) in Trauma Patients Presumed to Bleed (FIinTIC): Results from a Multicentre Double-Blind, Placebo-Controlled, Randomised, Pilot Trial

Background: Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. We evaluated the feasibility and efficacy of pre-hospital administration of fibrinogen concentrate to trauma patients bleeding or presumed to bleed. (FC; Clottafact®, LFB France). Methods: A prospective, randomised, placebo-controlled, double-blinded trial was conducted in Austria, Germany and the Czech Republic. Adult trauma patients aged ≥18 years with major bleeding and a need for volume therapy were eligible for enrolment. Patients were randomised to treatment with FC or placebo. The target FC dose of 50 mg/kg bodyweight or an equivalent amount of placebo was administered at the scene or during transportation to the study centre. The primary endpoint was blood clot stability as reflected by maximum clot firmness in the functional FIBTEM assay (FibMCF). The trial was registered with ClinicalTrials.gov, number NCT01475344 (FIinTIC-Trial). Findings: Between 2011 and 2015, 67 patients were enrolled, of whom 14 were excluded due to predefined exclusion criteria or missing data. Thus, the primary analysis included 53 patients, of whom 28 received FC group and 25 received placebo. Median FibMCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the emergency department, from 12.5 (interquartile range: 10.5-14) mm to 11 (9.5-13) mm, p=0.0226, but increased in the FC group from 13 (11-15) mm to 15 (13.5-17) mm, p=0.0062. The median between-group difference in the change in FibMCF was 5 (3-7) mm, p 200 mg/dl, throughout all observation time points. Interpretation: Early FC administration is feasible in the complex and time-sensitive environment of pre-hospital trauma care; it protects against early fibrinogen depletion and promotes rapid blood clot initiation and clot stability. Trial Registration Number: The trial was registered with ClinicalTrials.gov, number NCT01475344 (FIinTIC-Trial). Funding: The study was funded by LFB Biomedicaments (France), the US Army/Department of Defense (Coalition Warfare Grant) and the Austrian Ministry of Sports and Defence; the study medication and an unrestricted grant were provided by LFB Biomedicaments. In addition, the study was sponsored by the Medical University of Innsbruck (Austria). Declaration of Interest: BS has received travel grants, honoraria for speaking or participation at meetings from CSL Behring, BBraun and Biotest. BZ has received speaker fees from CSL Behring. DF has received study funding, honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Bayer, BBraun, Biotest, CSL Behring, Delta Select, Dade Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, Tem-Innovation. HS has received honoraria for participation in advisory board meetings for Bayer Healthcare, Bohringer Ingelheim and Tem International, and has received study grants from CSL Behring. MB has received research funding and travel grants from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, Mitsubishi Tanabe and non-financial support from TEM International outside the submitted work. MM has received fees for lectures, advisory board services, travel and research support from Astra Zeneca, Bayer, Biotest, CSL Behring, IL-Werfen and LFB Biomedicaments. HS has received honoraria for participation in advisory board meetings for Bayer Healthcare, Bohringer Ingelheim and Tem International, and has received study grants from CSL Behring. PI received non-financial (technical) support from TEM International GmbH during conduction of the study; personal fees from Baxter GmbH, CSL Behring GmbH, Fresenius Kabi GmbH Austria, Bayer Austria GmbH, LFB, and non-financial support from TEM International, outside the submitted work. WJM is employee of the US Army, Department of Defense, one of the funding organisations. BT, EO, HH, HT, MT, MK, WV, IZ, CaroN, ChriN and UM declare no conflict of interest. Ethical Approval: The study protocol was approved by the Medical Ethics Committee at each participating centre as well as by the national authorities of each participating country.