Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N3M5, Canada
NCT Number: NCT02203968
Trauma is the leading cause of death in people 44 years of age or younger. After major trauma, such as following high-speed motor vehicle collision, bleeding coupled with clotting defects is responsible for most of deaths in the first hours of hospital admission. Of note, these bleeding-related deaths are potentially preventable. Accordingly, the initial in-hospital management of severely injured patients focuses on stopping bleeding, replacing blood loss and correcting clotting defects.
Recently, animal and human research demonstrated that one of the major clotting defects following injury and bleeding is the drop in blood levels of fibrinogen (a clotting factor), which is detected on hospital admission in severely injured patients. These low fibrinogen levels are associated with increased blood transfusion and death. However, in North America, the standard of care for replacing low fibrinogen requires the use of cryoprecipitate, which is a frozen blood product with long preparation time, and similarly to other blood products, carries the risk of viral transmission and transfusion complications. Alternately, many Europeans countries where cryoprecipitate has been withdrawn from the market due to safety concerns, use fibrinogen concentrate. Fibrinogen concentrate undergoes pathogen inactivation, which is a process to eliminate the risk of transmitting viruses, bacteria and parasites, is likely a safer and faster alternative to cryoprecipitate. In Canada, fibrinogen concentrate is licensed for congenital low fibrinogen only.
Although preliminary data suggest that fibrinogen supplementation in trauma is associated with reduced bleeding, blood transfusion, and death, the feasibility, safety and efficacy of early fibrinogen replacement remains unknown. We proposed to conduct a feasibility randomized trial to evaluate the use of early fibrinogen concentrate against placebo in injured patients at our trauma centre.
A pilot trial is necessary to demonstrate the feasibility of rapidly preparing, delivering, and infusing fibrinogen concentrate as an early therapy to prevent excessive bleeding in trauma. This feasibility trial will provide preliminary safety and clinical outcome data to inform the design of larger trials; which ultimately aims to prevent bleeding-related deaths in the trauma population.
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Notify Me18 year and older
All sexes
Interventional
Phase 1 / Phase 2
Toronto, Ontario, M4N3M5, Canada
Healthy volunteers accepted: No
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
Exclusion criteria
i. Cardiogenic (myocardial or valvular dysfunction); ii. Distributive (septic, anaphylactic, acute adrenal insufficiency and neurogenic) and iii. Obstructive (cardiac tamponade, tension pneumothorax and massive pulmonary emboli).
i. Glasgow coma scale (GCS) of 3 due to severe traumatic brain injury (TBI); ii. TBI with clear indication of immediate neurosurgical intervention based on clinical findings (mechanism of trauma associated with focal signs such as anisocoria with fixed pupil) or on CT results (bleeding causing mass effect); iii. Unsalvageable head injury such as through-through gunshot wound to the head, open skull fracture with exposure/loss of brain tissue; as per the trauma team or neurosurgery initial clinical assessment or as per initial CT of the head findings;
Six grams of fibrinogen concentrate (RiaSTAP™) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.
Other names: RiaSTAP™
Placebo Comparator: Normal saline Placebo (normal saline) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.
Other names: Normal saline
Time frame: One year
1.Feasibility endpoint: 1.1Proportion of patients receiving study intervention (Fibrinogen Concentrate [FC] or placebo) within first hour of hospital admission. Based on the trial's sample size of 50 patients, feasibility is defined by 85% (96% confidence interval (CI) [72% - 98%]) of study participants receiving the study intervention within the first hour of hospital admission
Time frame: one year
Other feasibility endpoints:1.2.Proportion of patients receiving study intervention prior to any blood transfusion; 1.3.Times to randomization, issue, and start of infusion; 1.4.Duration of infusion; 1.5.Wastage of study intervention; 1.6.Proportion of patients with blood tests performed for all time points; 1.7.Proportion of missed patients (eligible but not randomized); 1.8.Randomization errors.
Physiologic endpoints: Plasma fibrinogen levels; Rotational Thromboelastometry/ Thromboelastography parameters (functional fibrinogen, fibtem, fibtem plus); plasmin anti-plasmin complex; tissue plasminogen activator; plasminogen activator inhibitor-1; d-dimer levels; international normalized ratio [INR]; partial thromboplastin time; complete blood count; endogenous thrombin potential; factor XIII; factor V; and activated protein C will be obtained on admission; and +1h, +3h, +11h, +23h & +47h following start time of study infusion
Time frame: one year
Rates of symptomatic thromboembolic complications in both study arms defined by the evidence of any of the following any time during hospital stay: deep venous thrombosis; myocardium infarction; cerebral vascular accident; pulmonary embolism; and arterial thrombosis
Rates of asymptomatic deep venous thrombosis by leg doppler at day 7 of hospital stay
Mortality by exsanguination
All-cause mortality at 28 days (mainly due to exsanguination; mainly neurological/ due to traumatic brain injury/ withdrawal of care; or mainly due to multiple organ failure/sepsis)
Incidence of acute lung injury/ acute respiratory distress syndrome before day 28
Multiple organ failure
Total amount of crystalloids used in 24h
Units of blood and blood products transfused in 24h of hospitalization
Sunnybrook Health Sciences Centre
Other
Fibrinogen in the Initial Resuscitation of Severe Trauma (FiiRST): a Randomized Feasibility Trial
Acronym: FiiRST
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