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
Condition: Reversal of Coagulopathy
MeSH terms: Hemostatic Disorders; Blood Coagulation Disorders
Intervention: Beriplex® P/N (Kcentra); Fresh frozen plasma
Intervention description: Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body-weight.; Intravenous infusion, dosage depending on baseline INR and body weight
Intervention MeSH terms: Protein C; Protein S
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 176.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anticoagulant reversal; Prothrombin Complex Concentrate; Coagulopathy; Coumarin derivatives; Emergency surgery; Invasive procedures; Vitamin K; Reversal of coagulopathy induced by coumarin derivatives; Kcentra

Summary:

      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.
    

Eligibility criteria:

        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