Efficacy and Safety Study of BERIPLEX® P/N (Kcentra) Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy

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 coumarin derivatives in subjects who require immediate correction of INR (International Normalized Ratio)and to stop an acute major bleeding.

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 Coumarin Derivatives in Subjects With Acute Major Bleeding

Conditions
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Blood Coagulation Disorders, Acute Major Bleeding

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 ≥ 18 years Subjects who have received oral vitamin K-antagonist therapy Subjects who have acute major bleeding, defined as one of the following: life-threatening or potentially life-threatening, acute bleeding associated with a fall in hemoglobin (Hb) level ≥ 2g/dL, bleeding requiring blood product transfusion INR ≥ 2 within 3 hours before start of study treatment Informed consent has been obtained Exclusion Criteria: Expected survival of less than 3 days, or expected surgery in less than 1 day Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control the acute bleeding event Use of unfractionated or low molecular weight heparin use from 24 hours prior to enrollment or expected need within 24 hours after start of infusion For patients with ICH: Glasgow coma score (GCS) < 7; intracerebral hematoma volume > 30cc as assessed by ABC/21; for subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm; for subarachnoid hemorrhage: any evidence of hydrocephalus; infratentorial ICH location; epidural hematomas; intraventricular extension of hemorrhage; modified Rankin score (mRS) of >3 prior to ICH History of thrombotic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within 3 months of enrollment Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies Suspected or confirmed sepsis at time of enrollment Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study Large blood vessel rupture (e.g. in advanced cancer patient) 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

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 of Stopping an Ongoing Major Bleed | Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 1 and 4 hours after the end of infusion. 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. | At 1 and 4 hours after the end of infusion | 
| Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR) | A rapid decrease of the international normalized ratio (INR) was defined as an INR ≤ 1.3 at 30 minutes after the end of the 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 end of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding | Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 3 and 6 hours after the start of infusion. 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. | At 3 and 6 hours after the start of infusion | 
| Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex | The incremental IVR [(IU/dL)/(IU/kg)] was calculated as follows: (IU/dL activity rise in plasma)/(IU/kg body weight infused) = [maximum increase in component plasma level within 3 hours compared to pre-infusion (IU/dL)]/{[exact dose of component in drug administered (IU)]/[body weight (kg)]}. | Before infusion and up to 3 h after the start of infusion | 
| 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 preinfusion until 24 h after the start of infusion | 
| 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 With INR Correction at Various Times After Randomization | The time taken from randomization to INR correction (defined as an INR ≤ 1.3) was recorded. The percentage of participants with INR correction was calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization. | From randomization until INR correction; calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization. | 
| Transfusion of Red Blood Cells | Red blood cells were packed red blood cells (PRBCs). | From the start of infusion until 24 h after the start of infusion | 
| Use of Other Blood Products and Hemostatic Agents | Other blood products and hemostatic agents containing coagulation factors (such as whole blood, plasma, albumin, platelets) not including PRBCs. | From the start of infusion until 24 h after the start of infusion | 
| 45-Day All-cause Mortality |  | Until Day 45 | 
| Overall Treatment-emergent Adverse Events (TEAEs) | Number of participants with TEAEs. Treatment-related AEs were defined as events whose relationship to study treatment was definitely related, probably related, or possibly related in the opinion of the investigator. AEs with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent SAEs. Deaths reported up to and including Day 45; one additional Beriplex death occurred after Day 45. | 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, induced by, coumarin, derivatives, Kcentra