Study of a Prothrombin Complex Concentrate for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Japanese Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy and safety of a Prothrombin Complex Concentrate (PCC), BE1116. BE1116 will be used for the rapid reversal of coagulopathy induced by vitamin K antagonists in Japanese subjects who require immediate correction of international normalized ratio (INR) due to a major bleed or emergency surgery.

Official Title
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An Open-label, Uncontrolled, Single-arm, Multicenter Phase IIIb Study to Assess the Efficacy and Safety of BE1116 in Japanese Subjects Receiving Vitamin K Antagonist Therapy With an Elevated INR and Either Acute Major Bleeding or a Requirement for Urgent Reversal of Vitamin K Antagonist Therapy for a Surgical or Invasive Medical Procedure

Conditions
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Acute Major Bleeding, Reversal of Coagulopathy

Intervention / Treatment
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* Biological: BE1116 (Prothrombin Complex Concentrate)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female Japanese subjects greater than or equal to 20 years Subjects currently on vitamin K antagonist (VKA) therapy INR greater than or equal to 2 within 3 hours before start of BE1116 infusion Urgent reversal of VKA therapy for a surgical or invasive medical procedure is required within 24 hours of the start of BE1116 infusion, or presentation with an acute major bleed Exclusion Criteria: Subjects for whom administration of I.V. vitamin K and VKA withdrawal, alone, can adequately correct the subject's coagulopathy before the infusion of BE1116 Subjects in whom lowering the INR to within the normal range is not a treatment goal Use of anticoagulants other than VKAs (or expected use within 1 day) Medical history for which PCCs are contraindicated History of thromboembolic event within 3 months of screening Congenital or acquired abnormality of hemostasis other than receipt of VKAs Administration of whole blood, plasma, plasma fractions, or platelets within 2 weeks prior to the start of BE1116 infusion For subjects with intracranial hemorrhage (ICH): Glasgow Coma Score (GCS) < 7 Intracerebral hematoma volume > 30 cm3 as assessed by computed tomography (CT) scan For subdural hematomas: maximum thickness ≥ 10 mm, midline shift ≥ 5 mm, or acute subdural hematomas (based on neurosurgeon review) For subarachnoid hemorrhage: any evidence of hydrocephalus, or Hunt and Hess Scale > 2, or concomitant subdural hematoma Infratentorial ICH location Epidural hematomas Intraventricular rupture of hemorrhage Requires surgical intervention

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BE1116<br>Single intravenous (I.V.) infusion, dosage depending on baseline INR and body weight | Biological: BE1116 (Prothrombin Complex Concentrate)<br> <br> * Other names: Confidex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With a Rapid Reversal of VKA Effect | A rapid reversal of (Vitamin K antagonist) VKA effect is a reduction of the INR to ≤ 1.3 at 30 minutes after the end of infusion. | At baseline and at 30 minutes after the end of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Achieving Hemostatic Efficacy During Surgery | Hemostatic efficacy is the binary endpoint of effective or non-effective hemostasis, where 'effective' is a hemostatic efficacy rating of very good or satisfactory, and 'non-effective' is a hemostatic efficacy rating of questionable or none. | From the start of surgery/procedure until the end of surgery/procedure | 
| Percentage of Subjects Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed | Hemostatic efficacy is the binary endpoint of effective or non-effective hemostasis, where 'effective' is a hemostatic efficacy rating of excellent or good, and 'non-effective' is a hemostatic efficacy rating of poor/none. | Baseline CT scan, baseline haematology or the end of infusion, until 24 hours after the end of infusion | 
| Increase in Plasma Levels of Factor (F)II, FVII, FIX, and FX, and Protein C and Protein S | The increase in plasma levels is assessed through response and in vivo recovery (IVR) of FII, FVII, FIX, FX, and protein C and protein S. The incremental IVR [(IU/dL)/(IU/kg)] is 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 | 
| Percentage of Subjects With INR Correction | The time taken from the start of infusion to INR correction (defined as an INR ≤ 1.3) is recorded. The percentage of participants with INR correction is calculated. | From the start of infusion until INR correction, up to 24 hours after the end of infusion | 
| Percentage of Subjects With INR Correction at Various Times After the End of Infusion | The time taken from the end of infusion to INR correction (defined as an INR ≤ 1.3) is recorded. The percentage of participants with INR correction at 0.5, 1, 3, 6, 12, and 24 h after the end of infusion is calculated. | From the end of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the end of infusion | 
| Percentage of Subjects Who Receive Red Blood Cells | Red blood cells are packed red blood cells (PRBCs). | From the start of infusion until 24 h after the start of infusion | 
| Percentage of Subjects Who Receive 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. TEAEs are defined as adverse events that developed or worsened following exposure to investigational medicinal product. Serious TEAEs are treatment-emergent serious adverse events (SAEs). | From the start of infusion up to the allowed time window of the Day 14 visit for non-serious AEs and from the start of infusion up to the allowed time window of the Day 45 visit for SAEs | 
| Mean modified Rankin Scale for all subjects with intracranial haemorrhage |  | Before infusion and at Day 45 | 
| Mean Predicted and Actual Blood Loss (mls) for all Surgical/Invasive Procedures |  | From the start of surgery/procedure until the end of surgery/procedure | 
| Mean Volume (mls) of Wound Drainage for all Surgical/Invasive Procedures |  | From the start of wound drainage until the end of wound drainage, up to the final safety follow-up visit (Day 45) | 
| Mean Time (mins) Between Last Suture and Cessation of Wound Drainage for all Surgical/Invasive Procedure |  | From the time of last suture until the end of wound drainage, up to the final safety follow-up visit (Day 45) | 
| Vital signs | Percentage of participants with a clinically significant change in vital signs (including blood pressure, respiratory rate, temperature and pulse rate) | At baseline and until 24 hours after the end of infusion | 
| Viral serology | Percentage of participants with negative viral serology (for Human immunodeficiency virus, Hepatitis B, Hepatitis A, Hepatitis C and Parvovirus B19) before infusion who become positive after infusion. | At baseline and until Day 45 |