Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate that Fibrinogen Concentrate (Human)(FCH) can reduce the amount of donor blood products needed during complex cardiovascular surgery, and that it is safe and well tolerated. Subjects in this study will get either a FCH or placebo infusion during surgery. This will be in addition to the standard treatment, which is donor blood or blood products. Placebo does not contain any effective medicine. The study is randomised. This means that the likelihood that subjects will get FCH or placebo is 50%. To make the comparison between FCH and placebo as fair as possible, the study is double blind. This means that neither the subjects nor the study doctor will know if FCH or placebo is administered. If necessary, the study doctor can find out which treatment the subjects are receiving.

Official Title
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REPLACE (Randomized Evaluation of Fibrinogen Versus Placebo in Complex Cardiovascular Surgery): a Prospective, Multinational, Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study for the Use of Fibrinogen Concentrate (Human) (FCH) in Complex Cardiovascular Surgery

Conditions
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Surgical Blood Loss, Postoperative Blood Loss

Intervention / Treatment
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* Biological: Fibrinogen Concentrate (Human) (FCH)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At Screening: Undergoing elective open surgical procedures on any part of the aorta requiring cardiopulmonary bypass (CPB), with or without other cardiac surgical procedures (e.g. valve replacement or repair, coronary artery bypass grafting, etc.). 18 years of age or older. Written informed consent for study participation obtained before undergoing any study specific procedures. Intraoperative (at the 1st 5-minute bleeding mass): A 5-minute bleeding mass of 60 to 250 g following discontinuation of CPB, administration of protamine, and establishment of surgical hemostasis. Minimum core body temperature 35°C, measured according to local practice. Activated clotting time ± 25% of baseline levels. Blood pH > 7.3. Exclusion Criteria: At Screening and/or baseline: Undergoing emergency aortic repair surgery. Reoperative aortic surgery at the same anatomic site as the original procedure such as replacement of a previously placed aortic graft. Resternotomy and rethoracotomy are permitted. Any operation for infection. Proof or suspicion of a congenital or acquired coagulation disorder (e.g. Von Willebrand's disease, hemophilia or severe liver disease) or a prothrombotic disorder (e.g. protein C or S deficiency). Myocardial infarction (MI), acute coronary syndrome or stroke in the 2 months preceding study surgery. Low molecular weight or unfractionated heparin in the 24 hours preceding study surgery. Clopidogrel administration within 5 days preceding study surgery or prasugrel administration within 7 days preceding study surgery or ticagrelor administration in the 48 hours preceding study surgery. Factor Xa inhibitors within 2 days preceding study surgery. IIb/IIIa antagonist administration in the 24 hours preceding study surgery. Use of direct thrombin inhibitors: within 3 days preceding study surgery for dabigatran and within 24 hours preceding study surgery for all others. An international normalized ratio > 1.3 immediately preceding the start of surgery. Intraoperative (at the 1st 5-minute bleeding mass): Use of any systemic hemostatic therapy (such as FFP, platelets, prothrombin complex concentrates) from the beginning of surgery until IMP administration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fibrinogen Concentrate (Human)<br> | Biological: Fibrinogen Concentrate (Human) (FCH)<br>* Single dose infused intravenously within 5 minutes of the completion of the measurement of the 5-minute bleeding mass; the dose is determined individually based on the measured maximum clot firmness (MCF) and subject body weight<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* Single dose of sodium chloride solution infused intravenously within 5 minutes at a volume equivalent to that needed for FCH<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total units of allogeneic blood products | Number of units administered of all allogeneic blood products combined (fresh frozen plasma, platelets, and red blood cells) | Up to 24 hours after investigational medicinal product (IMP) administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total avoidance of allogeneic blood transfusions | Number of subjects who are alive and do not have any administration of platelets, fresh frozen plasma (FFP), and red blood cells (RBCs) during the first 24 hours after administration of IMP | 24 hours after IMP administration | 
| Quantity of blood loss (6 hours) | Blood drainage volume from the chest | 6 hours after skin closure | 
| Quantity of blood loss (12 hours) | Blood drainage volume from the chest | 12 hours after skin closure | 
| Quantity of blood loss (24 hours) | Blood drainage volume from the chest | 24 hours after skin closure | 
| Change in bleeding mass | The 5-minute bleeding mass is measured as the difference in weight of surgical swabs after 5 minutes of surgical packing of the aortic surgical site. | Immediately before and 5 minutes after completion of IMP administration | 
| Mortality (Day 10) | Mortality with adjudicated cause of death up to 10 days after surgery | Up to 10 days after surgery | 
| Mortality (Day 30) | Mortality with adjudicated cause of death up to 30 days after surgery | Up to 30 days after surgery | 
| FFP consumption (24 hours) |  | 24 hours after IMP administration | 
| FFP consumption (10 days) |  | 10 days after IMP administration | 
| Platelet consumption (24 hours) |  | 24 hours after IMP administration | 
| Platelet consumption (10 days) |  | 10 days after IMP administration | 
| Red blood cells (RBC) consumption (24 hours) |  | 24 hours after IMP administration | 
| RBC consumption (10 days) |  | 10 days after IMP administration | 
| Total units of all allogeneic blood products (6 hours) | Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP | 6 hours after IMP administration | 
| Total units of all allogeneic blood products (12 hours) | Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP | 12 hours after IMP administration | 
| Volume of all allogeneic blood products (6 hours) | Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP | 6 hours after IMP administration | 
| Volume of all allogeneic blood products (12 hours) | Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 12 hours after administration of IMP | 12 hours after IMP administration | 
| Volume of all allogeneic blood products (24 hours) | Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 24 hours after administration of IMP | 24 hours after IMP administration | 
| Time from administration of study drug to completion of skin closure |  | Average 2 hours | 
| Mortality (24 hours) | Mortality with adjudicated cause of death during the first 24 hours after administration of IMP | WIthin 24 hours after IMP administration | 
| Peak plasma concentration of fibrinogen (Cmax) |  | At up to 10 time points from baseline and up to Day 11 after surgery. | 
| Maximum clot firmness |  | At baseline; on the day of surgery at: 30 min before CPB, the 1st 5 min bleeding mass, the end of IMP infusion, the 2nd 5-min bleeding mass, and closure; and on Day 2, 3, 4 and at the end of the study (discharge/Day 11 or at discontinuation if earlier). |