E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Elective spinal or abdominal surgery with expected major blood loss |
|
E.1.1.1 | Medical condition in easily understood language |
Acquired Fibrinogen deficiency |
|
E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051125 |
E.1.2 | Term | Hypofibrinogenaemia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main purpose of this phase III study is to demonstrate the efficacy of BT524 as a complementary therapy to management of uncontrolled severe hemorrhage in subjects undergoing elective major spinal or abdominal surgery.
The primary objective of this study is to demonstrate that BT524 is non-inferior that means not worse than fresh frozen plasma (FFP)/cryoprecipitate with a non-inferiority margin of 150 mL in reducing intra-operative blood loss by intravenous (IV) administration in subjects with acquired hypofibrinogenaemia undergoing elective major spinal or abdominal surgery.
If therapeutic equivalence has been demonstrated, therapeutic superiority of BT524 compared with FFP/cryoprecipitate will also be assessed.
|
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives are to demonstrate the efficacy of BT524 by assessing the correction of the fibrinogen level intra-operatively, the transfusion requirements, post-operative blood loss in the first 24 hours, the number of subjects with rebleeds, the hospital length of stay and the in-hospital mortality. Secondary objectives also comprise the safety of BT524 by documenting the number of adverse events (AE) including changes in laboratory parameters, the virus status, and the frequency and severity of thrombosis and of thromboembolic events (TEEs). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
At screening:
1.Written informed consent
2.Subjects scheduled for elective major spinal 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*
5.Intra-operative trigger for treatment:
a. Subjects undergoing spinal surgery: Intra-operative clinically relevant bleeding of approximately 1L, requiring hemostatic treatment during surgery**
b. Subjects undergoing cytoreductive PMP*surgery : Intra-operative prediction of clinically relevant bleeding of > 2 L, requiring hemostatic treatment during surgery***
*Inclusion criterion no. 4 aims to ensure that only subjects without hereditary bleeding disorders are to be included in this study. Subjects with continuous 'aspirin intake', subjects under Direct Oral Anti-Coagulants (DOACs), or with a hepatic disease are at higher bleeding risk. Nevertheless, these subjects can be included at the discretion of the investigator.
**A clinically relevant bleeding, resulting in a high risk for the need of fibrinogen supplementation with BT524 or FFP during surgery. The amount of clinically relevant blood loss depends on the subject's clinical condition, e.g. underlying disease, significant comorbidities, low body weight, relevant change of a laboratory value.
***Only applicable for subjects in the UK
|
|
E.4 | Principal 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 TEE in the preceding 6 months
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery as measured by amount of blood from the blood suction unit and amount of blood from surgical cloths and compresses. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery |
|
E.5.2 | Secondary end point(s) |
Efficacy:
Proportion (%) of subjects with successful correction of fibrinogen level 15 minutes after start of first IMP administration
• Time to first successful correction of fibrinogen level
• Total amount of transfusion products (allogenic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery
•Amount of red blood cells (allogenic and autologous RBCs) infused after start of first IMP administration until end of surgery
• post-operative blood loss in the first 24 hours
•Proportion (%) of subjects with rebleeds after the end of surgery until Day 8
•Hospital length of stay after surgery
•In-hospital mortality
Safety |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Until closing visit (up to 70 days) |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Switzerland |
United Kingdom |
European Union |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |