Adjusted Fibrinogen Replacement Strategy (AdFIrst)

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)

The main purpose of this study was to demonstrate the efficacy and safety of intraoperative use of fibrinogen concentrate BT524, as a complementary therapy for the management of uncontrolled severe hemorrhage in acquired hypofibrinogenemia. This non-inferiority study focused on the primary objective of demonstrating that BT524 is non-inferior that means not worse than the comparator fresh frozen plasma/cryoprecipitate in reducing intraoperative blood loss when administered intravenously in subjects with acquired hypofibrinogenemia undergoing elective major spinal or abdominal surgery.

Study Overview

• Status: Completed
• Conditions: Bleeding Disorder; Hypofibrinogenemia; Acquired
• Intervention / Treatment: Biological: BT524; Biological: FFP/Cryo

Detailed Description

Fibrinogen is the first coagulation factor to become critically reduced during intraoperative bleeding. Therefore, rapid supplementation of fibrinogen to restore physiological plasma levels is an important component in achieving and maintaining hemostasis in bleeding patients. In this study, subjects with major blood loss during elective spinal surgery or abdominal surgery were randomized to receive either intravenous transfusion of the fibrinogen concentrate BT524, or fibrinogen-containing fresh frozen plasma/cryoprecipitate as first hemostatic intervention to rapidly replenish fibrinogen and control bleeding.

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Jette, Belgium
    • Site 02
  • Leuven, Belgium
    • Site 01
• Czechia
  • Brno, Czechia
    • Site 54
  • Prague, Czechia
    • Site 51
  • Prague, Czechia
    • Site 53
  • Usti Nad Labem, Czechia
    • Site 52
• Germany
  • Bielefeld, Germany
    • Site 15
  • Bonn, Germany
    • Site 11
  • Hannover, Germany
    • Site 12
  • München, Germany
    • Site 14
  • Münster, Germany
    • Site 13
• Poland
  • Warschau, Poland
    • Site 21
• Spain
  • Barcelona, Spain
    • Site 31
  • Barcelona, Spain
    • Site 32
  • Barcelona, Spain
    • Site 33
  • Barcelona, Spain
    • Site34
• Switzerland
  • Liestal, Switzerland
    • Site 41
  • Zürich, Switzerland
    • Site 43
• United Kingdom
  • Basingstoke, United Kingdom
    • Site 71

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

At screening:

1. Written informed consent
2. Subjects scheduled for elective major spinal surgery or cytoreductive pseudomyxoma peritonei (PMP) surgery with expected major blood loss
3. Male or female, aged ≥ 18 years
4. No increased bleeding risk as assessed by standard coagulation tests and medical history

Intra-operative:

5.

1. Subjects who underwent spinal surgery: Intra-operative clinically relevant bleeding of approximately 1 Liter, requiring hemostatic treatment during surgery.
2. Subjects who underwent cytoreductive PMP surgery: Intra-operative prediction of clinically relevant bleeding of more than 2 Liter, requiring hemostatic treatment during surgery

Exclusion Criteria:

1. Pregnancy or unreliable contraceptive measures or breast feeding (women only)
2. Hypersensitivity to proteins of human origin or known hypersensitivity reactions to components of the Investigational Medicinal Products (IMP)
3. Participation in another clinical study within 30 days before entering the study or during the study and/or previous participation in this study
4. Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 30 days prior to infusion of IMP
5. Employee or direct relative of an employee of the Contract Research Organization (CRO), the study site, or Biotest
6. Inability or lacking motivation to participate in the study
7. 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
8. Presence or history of venous/arterial thrombosis or thromboembolic event (TEE) in the preceding 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BT524; Investigational Human Fibrinogen Concentrate	Biological: BT524; BT524 was administered intravenously at a patient specific dosage depending on the type of surgery, the extent of bleeding and the subject's clinical condition.; Other Names: Human Fibrinogen concentrate
Active Comparator: Fresh Frozen Plasma (FFP)/Cryoprecipitate (Cryo); Standard of Care	Biological: FFP/Cryo; FFP/Cryo was administered intravenously; dosage according to local standards. FFP, 15 mL per kg body weight (BW); Cryoprecipitate, fixed dose of 10 units.; Other Names: Fresh Frozen Plasma; Cryoprecipitate

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.	From decision to treat the subject with IMP until end of surgery, an average of 5 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion (%) of Subjects With Successful Correction of Fibrinogen Level (FIBTEM A10) 15 Minutes After Start of First IMP Administration	Successful correction of the fibrinogen level is defined as restoring fibrinogen FIBTEM A10 baseline (prior surgery) levels measured by ROTEM (thromboelastometry) 15 minutes after start of first IMP administration	Prior first dose, 15 minutes after start of first IMP administration
Time to First Successful Correction of Fibrinogen Level	Correction of the fibrinogen level, measured via thromboelastometry (ROTEM/FIBTEM A10), within 15 minutes after IMP start, between 15 and 90 minutes after IMP start, after 90 minutes after IMP start, or unsuccessful correction. The 4 categories were compared between the two treatment arms using a Chi-square test.	prior 1st dose, pre-dose, 15 minutes and 90 minutes after start of first IMP administration, end of surgery
Transfusion Requirements: Cell Salvage	Total amount of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Allogeneic Platelets	Total amount of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Allogeneic Red Blood Cells	Total amount of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Fresh Frozen Plasma	Total amount of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements, Cryoprecipitate	Total amount of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Amount of Red Blood Cells (RBCs)	Amount (volume) of RBCs (allogenic and autologous RBCs) infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.	After start of first IMP administration until end of surgery, an average of 5 hours
Post-operative Blood Loss	Post-operative drainage volume in the first 24 hours after end of surgery	From end of surgery (time of last suture) up to 24 hours after the end of surgery
Subjects With Rebleeds	Proportion (%) of subjects with rebleeds after the end of surgery until day 8	End of surgery up to 8 days after surgery
Hospital Length of Stay After Surgery	Length of stay after surgery (days) = 'date of hospital discharge' minus 'date of surgery'. Where date of discharge is the date of discharge following the IMP treated surgery.	From day of surgery until day of hospital discharge, an average of 16 days (up to 56 days)
In-hospital Mortality	Number and percentages of subjects who died during hospital stay	From day of surgery until day of hospital discharge, an average of 16 days (up to 56 days)
Number of Subjects With Thrombosis or Thromboembolic Events (TEEs)	Total number of subjects with thrombosis or TEEs documented as treatment-emergent adverse events of special interest	From day of surgery until closing visit (up to 181 days)
Change in Viral Status	Number of subjects with change in status of viral infections	Screening visit (up to 42 days prior to surgery) and closing visit (up to 181 days after surgery)

Collaborators and Investigators

• Sponsor: Biotest
• Collaborators: ICON Clinical Research; PRA Health Sciences
• Investigators: Principal Investigator: Niels Rahe-Meyer, Prof., Franziskus Hospital, Bielefeld

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2018
• Primary Completion (Actual): September 25, 2023
• Study Completion (Actual): November 21, 2023

Study Registration Dates

• First Submitted: December 19, 2017
• First Submitted That Met QC Criteria: February 22, 2018
• First Posted (Actual): February 23, 2018

Study Record Updates

• Last Update Posted (Actual): June 13, 2025
• Last Update Submitted That Met QC Criteria: May 28, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Fibrinogen
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Coagulation Disorders
• Other Study ID Numbers: 995; 2017-001163-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No