Back to resultsStudy of a Prothrombin Complex Concentrate for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Japanese Subjects
Primary Purpose
Acute Major Bleeding, Reversal of Coagulopathy
Status
Completed
Phase
Phase 3
Locations
Japan
Study Type
Interventional
Intervention
BE1116 (Prothrombin Complex Concentrate)
Sponsored by
About this trial
This is an interventional treatment trial for Acute Major Bleeding
Eligibility Criteria
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
Sites / Locations
- Nippon Medical School Hospital
- Kyushu Medical Center
- Nippon Medical School Chiba Hokusoh Hospital
- Kurashiki Central Hospital
- Osaka National Hospital
- Kinki University
- National Cerebral and Cardiovascular Center
- Tohoku University Hospital
- National Center for Global Health and Medicine
- Osaka University Hospital
- St. Luke's International Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
BE1116
Arm Description
Single intravenous (I.V.) infusion, dosage depending on baseline INR and body weight
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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".
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".
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)]}.
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.
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.
Percentage of Subjects Who Receive Red Blood Cells
Red blood cells are packed red blood cells (PRBCs).
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.
45-Day All-cause Mortality
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).
Mean modified Rankin Scale for all subjects with intracranial haemorrhage
Mean Predicted and Actual Blood Loss (mls) for all Surgical/Invasive Procedures
Mean Volume (mls) of Wound Drainage for all Surgical/Invasive Procedures
Mean Time (mins) Between Last Suture and Cessation of Wound Drainage for all Surgical/Invasive Procedure
Vital signs
Percentage of participants with a clinically significant change in vital signs (including blood pressure, respiratory rate, temperature and pulse rate)
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02281201
Brief Title
Study of a Prothrombin Complex Concentrate for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Japanese Subjects
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
March 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Major Bleeding, Reversal of Coagulopathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BE1116
Arm Type
Experimental
Arm Description
Single intravenous (I.V.) infusion, dosage depending on baseline INR and body weight
Intervention Type
Biological
Intervention Name(s)
BE1116 (Prothrombin Complex Concentrate)
Other Intervention Name(s)
Beriplex® P/N, KcentraTM, Confidex®
Primary Outcome Measure Information:
Title
Percentage of Subjects With a Rapid Reversal of VKA Effect
Description
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.
Time Frame
At baseline and at 30 minutes after the end of infusion
Secondary Outcome Measure Information:
Title
Percentage of Subjects Achieving Hemostatic Efficacy During Surgery
Description
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".
Time Frame
From the start of surgery/procedure until the end of surgery/procedure
Title
Percentage of Subjects Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed
Description
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".
Time Frame
Baseline CT scan, baseline haematology or the end of infusion, until 24 hours after the end of infusion
Title
Increase in Plasma Levels of Factor (F)II, FVII, FIX, and FX, and Protein C and Protein S
Description
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)]}.
Time Frame
Before infusion and up to 3 h after the start of infusion
Title
Percentage of Subjects With INR Correction
Description
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.
Time Frame
From the start of infusion until INR correction, up to 24 hours after the end of infusion
Title
Percentage of Subjects With INR Correction at Various Times After the End of Infusion
Description
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.
Time Frame
From the end of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the end of infusion
Title
Percentage of Subjects Who Receive Red Blood Cells
Description
Red blood cells are packed red blood cells (PRBCs).
Time Frame
From the start of infusion until 24 h after the start of infusion
Title
Percentage of Subjects Who Receive Other Blood Products and Hemostatic Agents
Description
Other blood products and hemostatic agents containing coagulation factors (such as whole blood, plasma, albumin, platelets) not including PRBCs.
Time Frame
From the start of infusion until 24 h after the start of infusion
Title
45-Day All-cause Mortality
Time Frame
Until Day 45
Title
Overall Treatment-emergent Adverse Events (TEAEs)
Description
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).
Time Frame
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
Title
Mean modified Rankin Scale for all subjects with intracranial haemorrhage
Time Frame
Before infusion and at Day 45
Title
Mean Predicted and Actual Blood Loss (mls) for all Surgical/Invasive Procedures
Time Frame
From the start of surgery/procedure until the end of surgery/procedure
Title
Mean Volume (mls) of Wound Drainage for all Surgical/Invasive Procedures
Time Frame
From the start of wound drainage until the end of wound drainage, up to the final safety follow-up visit (Day 45)
Title
Mean Time (mins) Between Last Suture and Cessation of Wound Drainage for all Surgical/Invasive Procedure
Time Frame
From the time of last suture until the end of wound drainage, up to the final safety follow-up visit (Day 45)
Title
Vital signs
Description
Percentage of participants with a clinically significant change in vital signs (including blood pressure, respiratory rate, temperature and pulse rate)
Time Frame
At baseline and until 24 hours after the end of infusion
Title
Viral serology
Description
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.
Time Frame
At baseline and until Day 45
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Program Director, Acquired Bleeding
Organizational Affiliation
CSL Behring
Official's Role
Study Director
Facility Information:
Facility Name
Nippon Medical School Hospital
City
Sendagi
State/Province
Bunkyo
ZIP/Postal Code
113-8603
Country
Japan
Facility Name
Kyushu Medical Center
City
Chuo-ku
State/Province
Fukuoka
ZIP/Postal Code
810-8563
Country
Japan
Facility Name
Nippon Medical School Chiba Hokusoh Hospital
City
Kamagari
State/Province
Inzai
ZIP/Postal Code
270-1694
Country
Japan
Facility Name
Kurashiki Central Hospital
City
Miwa
State/Province
Kurashiki
ZIP/Postal Code
710-0052
Country
Japan
Facility Name
Osaka National Hospital
City
Chuo-ku
State/Province
Osaka
ZIP/Postal Code
540-0006
Country
Japan
Facility Name
Kinki University
City
Higashiosaka
State/Province
Osaka
ZIP/Postal Code
577-0818
Country
Japan
Facility Name
National Cerebral and Cardiovascular Center
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0873
Country
Japan
Facility Name
Tohoku University Hospital
City
Aoba-ku
State/Province
Sendai
ZIP/Postal Code
980-8574
Country
Japan
Facility Name
National Center for Global Health and Medicine
City
Toyama
State/Province
Shinjuku
ZIP/Postal Code
162-0052
Country
Japan
Facility Name
Osaka University Hospital
City
Yamadaoka
State/Province
Suita
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
St. Luke's International Hospital
City
Chuo
State/Province
Tokyo
ZIP/Postal Code
104-8560
Country
Japan
12. IPD Sharing Statement
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Study of a Prothrombin Complex Concentrate for Rapid Reversal of Coagulopathy Induced by Vitamin K Antagonists in Japanese Subjects
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