Efficacy and Safety of Human Fibrinogen Concentrate in Managing Bleeding in Complex Cardiac Surgery with Cardiopulmonary Bypass: A Phase 3 Study

The primary objective of this study is to evaluate the efficacy of **fibrinogen concentrate (FGTW)** in combination with standard care in reducing the need for allogeneic transfusions within the first 24 hours after randomization in patients undergoing complex cardiac surgery involving cardiopulmonary bypass. This is clinically relevant as it aims to minimize the reliance on blood transfusions, which can reduce the risk of transfusion-related complications and improve patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of FGTW versus placebo in reducing the number and volume of red blood cell (RBC), fresh frozen plasma (FFP), and platelet concentrate transfusions between 24 hours after randomization and hospital discharge.
• Assessing the efficacy of FGTW versus placebo in reducing blood drainage volume within 12 hours after randomization.
• Determining the number of patients with total avoidance of allogeneic transfusions post-randomization.
• Evaluating the safety of FGTW.
• Assessing the impact of FGTW on mortality and surgical morbidity.
• Evaluating the duration of hospitalization in both treatment arms.
• Assessing the length of stay in the intensive care unit (ICU) in both treatment arms.

The clinical trial involves a total of **76 participants** who are adult patients aged **18 years and older**. The study population includes both **male and female** subjects undergoing complex cardiac surgery involving **cardiopulmonary bypass**. Participants were selected based on specific criteria, including undergoing planned complex cardiac surgery procedures, which exclude first-time isolated coronary artery bypass grafting, single valve repair/replacement, and repair of atrial septal defect. The trial population is characterized by a **FIBTEM MCF** of ≤10 mm during the last 20 minutes of cardiopulmonary bypass, and an investigational medicinal product dose requirement of ≤8 g, calculated based on the patient's weight and FIBTEM MCF value. All participants have provided informed consent and are covered by healthcare insurance as per local requirements. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel, phase 3 study to evaluate the efficacy and safety of fibrinogen concentrate (FGTW) in managing bleeding in patients undergoing complex cardiac surgery involving cardiopulmonary bypass (CPB). The primary objective is to assess the reduction in the need for allogeneic transfusions within the first 24 hours post-randomization. The trial is expected to commence recruitment on October 10, 2023, and conclude by April 30, 2026.

Participants will be involved in the study for a duration that includes pre-surgery screening, the surgical procedure, and follow-up visits. The inclusion visit, or screening, will determine eligibility based on criteria such as age (≥18 years), planned complex cardiac surgery involving CPB, and specific FIBTEM MCF values. The study will exclude individuals who do not meet these criteria. The primary endpoint is the number of units of allogeneic blood products administered within 24 hours post-randomization. Secondary endpoints include blood drainage volume, avoidance of allogeneic transfusions, and various measures of morbidity and mortality at specified intervals post-randomization.

Study visits will follow a structured sequence: the initial screening visit, the surgical procedure, and subsequent follow-up visits to monitor outcomes such as transfusion requirements and recovery metrics. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes like hospitalization duration and ICU stay. Participants may be withdrawn from the study if they experience adverse events, fail to comply with study procedures, or withdraw consent. The trial's design ensures rigorous assessment of the investigational product's efficacy and safety, maintaining scientific integrity and participant safety throughout the study duration.

The clinical trial involves the administration of **human fibrinogen** as the experimental medication. Human fibrinogen is a protein derived from human plasma, classified under the ATC code B02BB01. It is administered in the form of an intravenous infusion, with a pharmaceutical form designated as PHF675. The maximum daily dose and total dose amount are both set at 8.00 grams, with the treatment period limited to one day. The product is identified by the sponsor product code FGTW (or FGT1) and is not a pediatric formulation. The administration of human fibrinogen is intended to manage bleeding in patients undergoing complex cardiac surgery involving cardiopulmonary bypass (CPB).

In addition to the experimental treatment, the study utilizes a **0.9% Sodium Chloride Solution** as a placebo. This solution is administered via infusion and serves as a comparator treatment to evaluate the efficacy of the human fibrinogen. The sodium chloride solution does not contain any active pharmaceutical ingredients and is used to maintain the double-blind nature of the trial. The dosing schedule for the placebo mirrors that of the experimental treatment, ensuring consistency in administration and compliance monitoring across all study participants.

The efficacy of the fibrinogen concentrate (FGTW) in the management of bleeding in patients undergoing complex cardiac surgery will be assessed through a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 3 study. The primary efficacy endpoint is the number of units of allogeneic blood products, including red blood cells (RBC), fresh frozen plasma (FFP), and platelet concentrate, administered to patients between randomization and 24 hours thereafter. Secondary efficacy endpoints include blood drainage volume within 12 hours after randomization, the percentage of patients with total avoidance of allogeneic transfusions within 24 hours, and the number and volume of transfusion units infused between 24 hours after randomization and hospital discharge for each class of allogeneic blood product.

Additional secondary endpoints encompass mortality rates at 24 hours, 7 days, and 30 days post-randomization, the percentage of patients with surgical morbidity at these time points, and the percentage of patients with post-surgery stage 1 acute kidney injury (AKI). The study will also evaluate the percentage of patients requiring surgical re-exploration for bleeding within 24 hours, the percentage of patients with fibrinogen concentration below the lower limit of normal (LLN) from visit 2 to visit 5, and the percentage of patients receiving additional rescue therapies such as activated prothrombin complex concentrates (aPCC/PCCs), recombinant activated factor VII (rFVIIa), cryoprecipitate, or additional fibrinogen concentrate within 24 hours after randomization. The duration of hospitalization and length of stay in the intensive care unit (ICU) will also be recorded as part of the efficacy assessment.