Adjusted Fibrinogen Replacement Strategy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate efficacy and safety of fibrinogen concentrate BT524, when administered to patients with major blood loss during elective spine surgery.The study aims to demonstrate that BT524 is at least not worse than the comparator fresh frozen plasma in reducing intra-operative blood loss.

Detailed Description
-----------------
Fibrinogen is the first coagulation factor to become critically reduced during intra-operative bleeding. Therefore, rapid fibrinogen supplementation to restore physiological plasma levels is an important component to achieve and maintain hemostasis in bleeding patients. In this study, patients with major blood loss during elective spine surgery will be randomized 1:1 to a single intravenous transfusion of the fibrinogen concentrate BT524 or to fibrinogen-containing fresh frozen plasma (FFP).

Official Title
-----------------
A Randomized, Active-controlled, Multicenter, Phase III Study Investigating Efficacy and Safety of Intra-operative Use of BT524 (Human Fibrinogen Concentrate) in Subjects Undergoing Major Spinal or Abdominal Surgery (AdFIrst)

Conditions
-----------------
Bleeding Disorder, Hypofibrinogenemia; Acquired

Intervention / Treatment
-----------------
* Biological: BT524
* Biological: FFP/Cryo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At screening: Written informed consent Subjects scheduled for elective major spine surgery with expected major blood loss Male or female, aged ≥ 18 years No increased bleeding risk as assessed by standard coagulation tests and medical history Intra-operative: Intra-operative bleeding > 1,000 mL (total blood loss), resulting in a high risk for the need of FFP transfusion during surgery. Exclusion Criteria: Pregnancy or unreliable contraceptive measures or lactation period (women only) Hypersensitivity to proteins of human origin or known hypersensitivity reactions to components of the Investigational Medicinal Products (IMP) Participation in another clinical study within 30 days before entering the study or during the study and/or previous participation in this study Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 30 days prior to infusion of BT524 Employee or direct relative of an employee of the Contract Research Organization (CRO), the study site, or Biotest Inability or lacking motivation to participate in the study Medical condition, laboratory finding (e.g. clinically relevant biochemical or hematological findings outside the normal range), or physical exam finding that in the opinion of the investigator precludes participation Presence or history of venous/arterial thrombosis or TEE in the preceding 6 months -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are randomly assigned to treatment with BT524 or FFP/Crypo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BT524<br>Investigational Human Fibrinogen Concentrate | Biological: BT524<br>* BT524 is administered intravenously, patient specific dosage calculated based on body weight and fibrinogen level.<br>* Other names: Human Fibrinogen concentrate;|
| Active Comparator: Fresh Frozen Plasma (FFP)/Cryoprecipitate (Cryo)<br>Standard of Care | Biological: FFP/Cryo<br>* FFP/Cryo is administered intravenously; dosage according to local standards in mL per kg body weight.<br>* Other names: Fresh Frozen Plasma;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-operative blood loss | Intra-operative blood loss as measured by amount of blood from blood suction unit and amount of blood from surgical cloths and compresses. | Decision to treat until end of surgery, expected average of 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correction of the fibrinogen level | Proportion (%) of subjects with successful correction of fibrinogen level | 15 minutes after start of IMP administration | 
| Transfusion requirements | Total amount of transfusion products | After end of IMP administration until end of surgery, expected average of 2 hours | 
| 24 hours post-operative blood loss | Drainage volume | 1 day after surgery | 
| Subjects with rebleeds | Proportion (%) of subjects | 8 days after surgery | 
| Hospital length of stay | Days in hospital after surgery | 35 days after surgery | 
| In-Hospital mortality | Number of death during hospital stay | 35 days after surgery | 
| Adverse events | Number of adverse events | 35 days after surgery | 
| Virus status | Number of subjects with viral infection | 35 days after surgery | 
| Thrombosis and of thromboembolic events | Frequency and severity | 35 days after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fibrinogen