An Open-label, Randomized, Multicenter Phase IIIb Study to Assess the Efficacy, Safety and Tolerance of BERIPLEX® P/N (Kcentra) Compared With Plasma for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Subjects Requiring an Urgent Surgical Procedure

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy, safety and tolerance of Beriplex® P/N (Kcentra) compared with plasma in regard to rapid reversal of coagulopathy induced by vitamin K antagonists in subjects who require immediate correction of international normalized ratio (INR) because of emergency surgery.

Official Title
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An Open-label, Randomized, Multicenter Phase IIIb Study to Assess the Efficacy, Safety and Tolerance of BERIPLEX® P/N Compared With Plasma for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Subjects Requiring an Urgent Surgical Procedure

Conditions
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Reversal of Coagulopathy

Intervention / Treatment
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* Biological: Beriplex® P/N (Kcentra)
* Biological: Fresh frozen plasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects greater than or equal to 18 years, Subjects currently on oral vitamin K antagonist (VKA) therapy, An urgent surgical procedure is required within 24 hours of the start of investigational medicinal product (IMP), Due to the nature of the procedure, withdrawal of oral VKA therapy and infusion of plasma are also indicated to reverse the VKA effect, INR greater than or equal to 2 within 3 hours before start of IMP, Informed consent has been obtained. Exclusion Criteria: Subjects requiring urgent surgical procedures where according to the surgeon's clinical judgment, an accurate estimate of blood loss is not possible (e.g., ruptured aneurysm), Subjects for whom administration of intravenous vitamin K and vitamin K antagonists withdrawal alone can adequately correct the subject's coagulopathy before initiation of the urgent surgical procedure, Administration of intravenous vitamin K more than 3 hours or administration of oral vitamin K more than 6 hours prior to infusion of IMP, Subjects in whom lowering INR within normal range may present an unacceptable risk for a thromboembolic complication where the INR goal is to lower but not normalize the INR because of risk of a procedure-associated stroke, Subjects, who despite medical management that includes close monitoring and diuretics, may not, by investigator assessment, tolerate the total volume of IMP required by the protocol, Expected need for additional non-study blood products before infusion of IMP (Note: Administration of packed red blood cells is not an exclusion criterion), Expected need for platelet transfusions or desmopressin before Day 10, Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control or resolve an acute bleeding complication and/or control the acute bleeding event, Unfractionated or low molecular weight heparin use within 24 hours before randomization or potential need before completion of the procedure, History of thromboembolic event, myocardial infarction, unstable angina pectoris, critical aortic stenosis, cerebral vascular accident, transient ischemic attack, severe peripheral vascular disease, disseminated intravascular coagulation within 3 months of enrollment, Reversal of VKA therapy alone may not resolve the coagulopathy (eg, receiving a potent anti-platelet agent, i.e., clopidogrel or prasugrel, or advanced liver disease), Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies, Suspected or confirmed serious viral or bacterial infection, e.g., meningitis, or sepsis at time of enrollment, Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study (Note: Administration of packed red blood cells is not an exclusion criterion), Pre-existing progressive fatal disease with a life expectancy of less than 2 months, Known inhibitors to coagulation factors II, VII, IX, or X; or hereditary protein C or protein S deficiency; or heparin-induced, type II thrombocytopenia, Treatment with any other investigational medicinal product within 30 days prior to inclusion into the study, Presence or history of hypersensitivity to components of the study medication, Pregnant or breast-feeding women, Prior inclusion in this study or any other CSL Behring sponsored Beriplex study, For subjects with intracranial hemorrhage with: Glasgow Coma Score <10 (see Appendix 8) Modified Rankin Score > 3 prior to ICH (see Appendix 9) Intracerebral hemorrhage Epidural hematomas Infratentorial hemorrhage Subarachnoid hemorrhage (SAH) subjects with a Hunt and Hess Scale >2 Subdural hematomas that: are judged to be an acute subdural hematoma (based on neurosurgeon review) have a concurrent SAH or parenchymal contusion

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Beriplex® P/N<br> | Biological: Beriplex® P/N (Kcentra)<br>* Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body-weight.<br>* Other names: Kcentra;|
| Active Comparator: Fresh frozen plasma<br> | Biological: Fresh frozen plasma<br>* Intravenous infusion, dosage depending on baseline INR and body weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Hemostatic Efficacy During Surgery | Hemostatic efficacy was rated as excellent, good, or poor/none, based on prespecified definitions. Hemostatic efficacy was the binary endpoint of effective or non-effective hemostasis, where 'effective' was a hemostatic efficacy rating of excellent or good, and 'non-effective' was a hemostatic efficacy rating of poor/none. | From the start of infusion until the end of surgery | 
| Percentage of Participants Who Had a Rapid Decrease of the INR | A rapid decrease of the INR was defined as an INR ≤ 1.3 at 30 minutes after the end of infusion. The INR is a standard way to describe the time it takes for blood to clot; an INR range of 0.8 to 1.2 is considered normal for a healthy person who is not using oral anticoagulant therapy. | 30 minutes after the end of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S | Plasma levels are presented as the percentage of normal at pre-infusion and 30 min and 24 h after the start of infusion. The plasma level assay results are reported as a potency relative to a standard, where 100% is considered to be normal. | From pre-infusion until 24 h after the start of infusion | 
| Transfusion of Packed Red Blood Cells (PRBCs) or Whole Blood | The total units of transfused PRBCs or whole blood | From the start of surgery until 24 h after the start of surgery | 
| Percentage of Participants With INR Correction at Various Times After the Start of Infusion | The time taken from the start of infusion to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion. | From the start of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion | 
| Percentage of Participants Who Received Red Blood Cells | Red blood cells were PRBCs and whole blood | From the start of surgery until 24 h after the start of surgery | 
| Overall Treatment-emergent Adverse Events (TEAEs) | Number of participants with TEAEs. TEAEs were defined as adverse events that developed or worsened following exposure to investigational medicinal product. Treatment-related TEAEs were events whose relationship to study treatment was related, probably related, or possibly related in the opinion of the investigator. Treatment emergent adverse events with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent serious adverse events (SAEs). | From the start of infusion up to the allowed time window of the Day 10 visit for non-serious AEs and from the start of infusion up to the allowed time window of the Day 45 visit for SAEs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anticoagulant reversal, Prothrombin Complex Concentrate, Coagulopathy, Coumarin derivatives, Emergency surgery, Invasive procedures, Vitamin K, Reversal of coagulopathy induced by coumarin derivatives, Kcentra