Bleeding DisorderPhase 3AdFIrstNCT03444324
Adjusted Fibrinogen Replacement Strategy
A Phase 3 study testing BT524 and FFP/Cryo in people with Bleeding Disorder and Hypofibrinogenemia; Acquired, run by Biotest at 19 sites in 7 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Bleeding Disorder, Hypofibrinogenemia; Acquired
- What is being tested?
- BT524 and FFP/Cryo
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 222 participants
- Where
- 19 sitesin 7 countries
- Study dates
- 3 Apr 2018to 21 Nov 2023
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- At screening:
- Written informed consent
- Subjects scheduled for elective major spinal surgery or cytoreductive pseudomyxoma peritonei (PMP) 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:
Show all 9Show fewer
- 5.
- Subjects who underwent spinal surgery: Intra-operative clinically relevant bleeding of approximately 1 Liter, requiring hemostatic treatment during surgery.
- Subjects who underwent cytoreductive PMP surgery: Intra-operative prediction of clinically relevant bleeding of more than 2 Liter, requiring hemostatic treatment during surgery
Who cannot join
- Pregnancy or unreliable contraceptive measures or breast feeding (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 IMP
- 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 thromboembolic event (TEE) in the preceding 6 months
Trial locations and contacts
19 sites in 7 countries.
19 sites in 7 countries
Germany5 sites
Site 15
Bielefeld
Site 11
Bonn
Site 12
Hanover
Site 14
München
Site 13
Münster
Spain4 sites
Site 31
Barcelona
Site 32
Barcelona
Site 33
Barcelona
Site34
Barcelona
About this study
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)
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.
Read the 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.
- Conditions
- Bleeding Disorder, Hypofibrinogenemia; Acquired
- Being tested
- BT524, FFP/Cryo
- Keywords
- Fibrinogen
- Medical subject headings
- Hemostatic Disorders, Afibrinogenemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BT524Biological
Also called Human Fibrinogen concentrate
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.
FFP/CryoBiological
Also called Fresh Frozen Plasma, Cryoprecipitate
FFP/Cryo was administered intravenously; dosage according to local standards. FFP, 15 mL per kg body weight (BW); Cryoprecipitate, fixed dose of 10 units.
| Study group | Role | What they receive |
|---|---|---|
| BT524 | Experimental | Investigational Human Fibrinogen Concentrate Receives: Biological: BT524 |
| Fresh Frozen Plasma (FFP)/Cryoprecipitate (Cryo) | Active comparator | Standard of Care Receives: Biological: FFP/Cryo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From decision to treat the subject with IMP until end of surgery, an average of 5 hours
Secondary outcomes (14)
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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: Screening visit (up to 42 days prior to surgery) and closing visit (up to 181 days after surgery)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2018
- Study start3 Apr 2018
- Primary completion25 Sep 2023
- Study completion21 Nov 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Bleeding DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients were randomly assigned to treatment with BT524 or FFP/Cryo.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 222 participants (actual)
Sponsor and investigators
- Lead sponsor
- Biotest
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- PRA Health Sciences, ICON Clinical Research
- Responsible party
- Sponsor
- Investigators
- Niels Rahe-Meyer, Prof., Principal investigator, Franziskus Hospital, Bielefeld
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03444324
- Sponsor's protocol ID
- 995
- Other IDs
- 2017-001163-20, 2017
- Acronym
- AdFIrst
- Status last verified
- May 2025
- First submitted
- 19 Dec 2017
- Last updated
- 13 Jun 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roy A, Stanford S, Cecil T, Preston N, Rowley J, Porter P, Schimo S, Abraha S, Staus A, Balaban U, Wessels-Kranz J, Schuttrumpf J, Aigner S, Bohm H, Rahe-Meyer N. Efficacy and safety of fibrinogen concentrate (BT524) in severe hemorrhage: Phase 3 subcohort analysis of the AdFIrst trial in patients undergoing cytoreductive surgery for pseudomyxoma peritonei. J Clin Anesth. 2026 Jul;113:112242. doi: 10.1016/j.jclinane.2026.112242. Epub 2026 Jun 5.
PubMed 42247815Rahe-Meyer N, Roy A, Trouillier HH, Schimo S, Wessels-Kranz J, Abraha S, Staus A, Balaban U, Hader T, Schuttrumpf J, Aigner S, Bohm H. Efficacy and safety of human fibrinogen concentrate (BT524) in patients with major haemorrhage undergoing major orthopaedic or abdominal surgery (AdFIrst): a randomised, active-controlled, multicentre, partially blinded, phase 3 non-inferiority trial. EClinicalMedicine. 2025 Jun 7;85:103264. doi: 10.1016/j.eclinm.2025.103264. eCollection 2025 Jul.
PubMed 40741224
Study at a glance
From the registry record, last updated by the sponsor on 13 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03444324
- Acronym / sponsor ID
- AdFIrst / 995
- Conditions
- Bleeding Disorder, Hypofibrinogenemia; Acquired
- Keywords
- Fibrinogen
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 222 participants (actual)
- Lead sponsor
- BiotestIndustry (pharma, biotech, devices)
- Collaborators
- PRA Health Sciences, ICON Clinical Research
- Study start
- 3 Apr 2018 (actual)
- Primary completion
- 25 Sep 2023 (actual)
- Study completion
- 21 Nov 2023 (actual)
- First posted
- 23 Feb 2018 (actual)
- Results
- Posted 13 Jun 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Patients were randomly assigned to treatment with BT524 or FFP/Cryo.
| Arm | Type | Receives |
|---|---|---|
| BT524 | Experimental | Biological: BT524Investigational Human Fibrinogen Concentrate |
| Fresh Frozen Plasma (FFP)/Cryoprecipitate (Cryo) | Active comparator | Biological: FFP/CryoStandard of Care |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Written informed consent
- Subjects scheduled for elective major spinal surgery or cytoreductive pseudomyxoma peritonei (PMP) 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
- 5.
Key exclusion criteria (8 listed)
- Pregnancy or unreliable contraceptive measures or breast feeding (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 IMP
- Employee or direct relative of an employee of the Contract Research Organization (CRO), the study site, or Biotest
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BT524Also: Human Fibrinogen concentrateBT524 was administered intravenously at a patient specific dosage depending on the type of surgery, the extent of bleeding and the subject's clinical condition. | Biological | BT524 |
| FFP/CryoAlso: Fresh Frozen Plasma, CryoprecipitateFFP/Cryo was administered intravenously; dosage according to local standards. FFP, 15 mL per kg body weight (BW); Cryoprecipitate, fixed dose of 10 units. | Biological | Fresh Frozen Plasma (FFP)/Cryoprecipitate (Cryo) |
Primary outcome
Intra-operative Blood Loss
Time frame: From decision to treat the subject with IMP until end of surgery, an average of 5 hours
Intra-operative blood loss as measured by amount of blood from blood suction unit and amount of blood from surgical cloths and compresses.
14 secondary outcomes
Proportion (%) of Subjects With Successful Correction of Fibrinogen Level (FIBTEM A10) 15 Minutes After Start of First IMP Administration
Time frame: Prior first dose, 15 minutes after start of first IMP administration
Time to First Successful Correction of Fibrinogen Level
Time frame: prior 1st dose, pre-dose, 15 minutes and 90 minutes after start of first IMP administration, end of surgery
Transfusion Requirements: Cell Salvage
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Allogeneic Platelets
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Allogeneic Red Blood Cells
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements: Fresh Frozen Plasma
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Transfusion Requirements, Cryoprecipitate
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Amount of Red Blood Cells (RBCs)
Time frame: After start of first IMP administration until end of surgery, an average of 5 hours
Post-operative Blood Loss
Time frame: From end of surgery (time of last suture) up to 24 hours after the end of surgery
Subjects With Rebleeds
Time frame: End of surgery up to 8 days after surgery
Hospital Length of Stay After Surgery
Time frame: From day of surgery until day of hospital discharge, an average of 16 days (up to 56 days)
In-hospital Mortality
Time frame: 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)
Time frame: From day of surgery until closing visit (up to 181 days)
Change in Viral Status
Time frame: Screening visit (up to 42 days prior to surgery) and closing visit (up to 181 days after surgery)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jun 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42247815Roy A, Stanford S, Cecil T, Preston N, Rowley J, Porter P, Schimo S, Abraha S, Staus A, Balaban U, Wessels-Kranz J, Schuttrumpf J, Aigner S, Bohm H, Rahe-Meyer N. Efficacy and safety of fibrinogen concentrate (BT524) in severe hemorrhage: Phase 3 subcohort analysis of the AdFIrst trial in patients undergoing cytoreductive surgery for pseudomyxoma peritonei. J Clin Anesth. 2026 Jul;113:112242. doi: 10.1016/j.jclinane.2026.112242. Epub 2026 Jun 5.
- Derived from this study: PubMed 40741224Rahe-Meyer N, Roy A, Trouillier HH, Schimo S, Wessels-Kranz J, Abraha S, Staus A, Balaban U, Hader T, Schuttrumpf J, Aigner S, Bohm H. Efficacy and safety of human fibrinogen concentrate (BT524) in patients with major haemorrhage undergoing major orthopaedic or abdominal surgery (AdFIrst): a randomised, active-controlled, multicentre, partially blinded, phase 3 non-inferiority trial. EClinicalMedicine. 2025 Jun 7;85:103264. doi: 10.1016/j.eclinm.2025.103264. eCollection 2025 Jul.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Niels Rahe-Meyer, Prof. principal investigator
Franziskus Hospital, Bielefeld
19 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing BT524 and FFP/Cryo in people with Bleeding Disorder and Hypofibrinogenemia; Acquired, run by Biotest at 19 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Germany, Czechia, Spain, Belgium, Switzerland and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Intra-operative Blood Loss (time frame: From decision to treat the subject with IMP until end of surgery, an average of 5 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03444324, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jun 2025.