A prospective, randomized controlled trial of fibrinogen concentrate (FC) plus standard of care versus standard of care alone in adult trauma patients with major bleeding or presumed major bleeding is developed to evaluate the efficacy and safety of prehospital administration of FC in trauma patients with suspected hypofibrinogenemia and active bleeding or presumed to be bleeding.

The main endpoints are:

1. Plasma fibrinogen levels in the first blood sample drawn at the patient's arrival at the trauma room and/or similar emergency bay dedicated to trauma and reanimation above the critical threshold of 2.0 g/l. As fibrinogen decreases early in trauma, its deficiency predicts massive bleeding and death.
2. Administration feasibility of FC within the prehospital setting.

Patients will be randomly assigned to receive either standard trauma care or standard trauma care plus administration of FC.

Pre-hospital Administration of Fibrinogen Concentrate in Patients with Suspected Trauma-Induced Coagulopathy (PAF-TIC)

Introduction Trauma is a leading cause of morbidity and mortality worldwide, with hemorrhage being one of the primary preventable factors contributing to trauma-related deaths. The management of trauma induced coagulopathy (TIC) is a critical aspect of the resuscitation of severely injured patients. Fibrinogen, a key factor in the coagulation cascade, is often rapidly depleted in cases of severe trauma, leading to compromised clot formation and stability. The use of fibrinogen concentrate (FC) in the pre-hospital setting has emerged as a potential intervention to address this issue and improve patient outcomes.

Recent studies have explored the feasibility, efficacy, and safety of administering FC in both prehospital and emergency departments . A randomized feasibility trial demonstrated that early infusion of FC is attainable and can increase plasma fibrinogen concentration during trauma resuscitation, suggesting that larger trials are justified. Similarly, a prospective, randomized, placebo-controlled trial found that prehospital administration of FC improved blood clot stability and protected against early fibrinogen depletion. These findings are supported by a systematic review, which, despite methodological limitations, indicated that FC administration may reduce the need for blood product transfusion.

In a recently published Australian prehospital study, significant coagulopathy was found to develop in 36% of patients transported to trauma centers and could be found in some patients as early as within 30 minutes of injury. Low fibrinogen was the commonest coagulopathy found among trauma patients and was linked to higher in-hospital mortality rates and an increased need for blood transfusions.

Previous retrospective analyses have provided insights into the effects of FC therapy on fibrinogen levels post-trauma, suggesting that FC does not lead to higher fibrinogen levels beyond the natural acute phase response following tissue injury. Goal-directed coagulation management using thromboelastometry-guided administration of FC has also been associated with favorable survival rates, although the need for prospective, randomized trials has been emphasized.

The ongoing debate regarding the optimal method for fibrinogen replacement in traumatic hemorrhage highlights the importance of further research. While some studies have shown improved survival rates at specific time points following FC administration, the overall impact on hospital mortality remains unclear. The targeted use of FC guided by rotational thromboelastometry has been proposed as a rapid and feasible method to replace fibrinogen, but large multicenter randomized controlled trials are needed to provide conclusive evidence.

Considering these findings, developing a protocol for FC use in the prehospital setting for trauma patients is of paramount importance. Such a protocol would potentially set a standard for FC administration, ensure timely and effective management of TIC, improve the chances of survival and recovery for trauma patients, and optimize the use of blood components and blood-derived products.

Objective To evaluate the efficacy and safety of prehospital administration of FC in trauma patients with suspected hypofibrinogenemia and active bleeding or presumed to be bleeding.

Design A prospective, randomized controlled trial of fibrinogen concentrate plus standard of care versus standard of care alone in adult trauma patients with major bleeding or presumed major bleeding.

Setting Prehospital emergency services from university-affiliated hospitals and regional hospital centers, as well as Helicopter Emergency Medical coordinated by the National Institute of Medical Emergency.

Participants Adult trauma patients with major bleeding and shock, defined by Shock Index, and high likelihood of requiring massive transfusion, defined by mTICCS score.

Stratification Stratification ensures that each treatment group (FC vs. placebo) is balanced in terms of trauma severity. This balance is crucial for minimizing bias and confounding, allowing for a clearer assessment of FC's impact on primary outcomes. During the randomization process, participants should be stratified based on their Injury Severity Score (ISS). ISS is a widely used scoring system to assess trauma severity, with higher scores indicating more severe injuries. Stratification can be achieved by categorizing ISS into predefined ranges (e.g., mild: 1-8, moderate: 9-15, severe: >15).

Interventions Patients will be randomly assigned to receive either standard trauma care or standard trauma care plus administration of FC. The standard of care is determined by national guidelines on trauma, elaborated by the National Institute of Medical Emergency and taught to prehospital physicians and nurses at the time of enrollment in prehospital teams to ensure consistency in the treatment of trauma patients nationwide . The patients assigned to the intervention arm will receive the administration of a fixed dose of 4g fibrinogen, as per previous studies.

Safety Monitoring Adverse events, including thromboembolic events, will be monitored and recorded up to 7 days after hospital admission. A Data Safety Monitoring Board (DSMB) will be established to oversee the trial's safety aspects.

Statistical Analysis Descriptive statistics will be used to summarize patient characteristics. The primary and secondary outcomes will be compared between the FC group and standard of care groups using appropriate statistical tests. Subgroup analyses will be performed based on the severity of the injury, baseline fibrinogen levels at admission, and area of lesions.

Statistical Analysis Plan Sample size calculations: By using an effect size of 0.7, a significance level of 0.1, and a power of 0.8, the required sample size is 26 patients per intervention arm, corresponding to a total sample size of 52 patients

Statistical Methods

• Statistics: Summarize the study population's baseline characteristics (e.g., age, gender, and Injury Severity Score). Means and standard deviations will be reported for continuous variables, while frequencies and percentages will be reported for categorical variables.
• Comparative Analysis: For continuous outcomes, independent t-tests or Mann-Whitney U tests will be used depending on the normality of the data. For categorical outcomes (e.g., incidence of thromboembolic events, mortality rates), chi-square tests or Fisher's exact tests will be used.
• Regression Analysis: Multivariate regression models will be applied to adjust for potential confounders and to identify independent predictors of outcomes.
• Survival Analysis: Kaplan-Meier curves will be constructed for survival data, and differences between groups will be assessed using the log-rank test. Cox proportional hazard models will be used to adjust for covariates.

Handling of Missing Data

Missing data will be handled using the following strategies:

• Complete Case Analysis: Initially, analyses will be conducted on complete cases only.
• Multiple Imputation: If the proportion of missing data is significant, multiple imputation techniques will be used to handle missing values, assuming that the data are missing at random (MAR).
• Sensitivity Analysis: Sensitivity analyses will be performed to assess the robustness of the findings to different methods of handling missing data (e.g., complete case analysis, multiple imputation).

Intention-to-Treat Analysis An intention-to-treat (ITT) analysis will be performed to ensure that all randomized participants are included in the analysis according to the group they were originally assigned, regardless of whether they completed the intervention as per protocol. This approach maintains the benefits of randomization and provides an unbiased estimate of the treatment effect.

Interim Analysis

An interim analysis will be conducted when 50% of the participants have been enrolled and followed up for the primary outcome. The purpose of the interim analysis is to:

• Assess the safety and efficacy of the intervention.
• Make decisions regarding the continuation, modification, or termination of the study based on predefined stopping rules.

A DSMB will oversee the interim analysis and will have the authority to recommend stopping the trial if there is clear evidence of benefit or harm.

Subgroup analyses

Subgroup analyses will be performed to evaluate the consistency of the treatment effect across different patient subgroups. These subgroups may include:

• Severity of injury (stratified by Injury Severity Score).
• Baseline fibrinogen levels (e.g., above or below median level).
• Age groups.
• Gender. These analyses will be pre-specified and interpreted with caution to avoid over- interpretation of findings due to multiple comparisons.

Adjustment for Multiple Comparisons To address the issue of multiple comparisons and control the family-wise error rate, the Bonferroni correction will be applied. If there are comparisons, the significance level for each test will be adjusted to α/k. Alternatively, the False Discovery Rate (FDR) method may be used to control for the proportion of false positives among the significant findings.

The Statistical Analysis Plan for the study will provide a comprehensive framework to ensure rigorous and transparent analysis of the data. The plan includes robust methods for handling missing data, performing intention-to-treat analysis, conducting interim and subgroup analyses, and adjusting for multiple comparisons. This thorough approach will help to ensure the reliability and validity of the study findings, contributing to the evidence base for prehospital administration of fibrinogen concentrate in trauma patients.

Inclusion Criteria:

• Adult patients at risk of Trauma Induced Coagulopathy (TIC), with major bleeding or presumed to be bleeding, identified by TIC criteria: mTICCS score > 5 or Shock index > 0.8.

Exclusion Criteria:

• Known adverse reactions to fibrinogen concentrate (FC)
• Isolated trauma such as traumatic head injury only
• Need for cardiopulmonary resuscitation (CPR) on the scene or peri-arrest scenarios
• Deep hypothermia
• Age below 18 years
• Pregnancy
• Prothrombin time ratio superior equal or superior to 1.2 (PTr>1.2) at the hospital admission
• Refusal to participate (if the patients are capable of consenting)

Masking will be applied to participants during all the stay and to care providers until randomly opaque envelopes are opened.