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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Major Bleeding; Reversal of Coagulopathy
• Intervention / Treatment: Biological: BE1116 (Prothrombin Complex Concentrate)

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Bunkyo
    • Sendagi, Bunkyo, Japan, 113-8603
      • Nippon Medical School Hospital
  • Fukuoka
    • Chuo-ku, Fukuoka, Japan, 810-8563
      • Kyushu Medical Center
  • Inzai
    • Kamagari, Inzai, Japan, 270-1694
      • Nippon Medical School Chiba Hokusoh Hospital
  • Kurashiki
    • Miwa, Kurashiki, Japan, 710-0052
      • Kurashiki Central Hospital
  • Osaka
    • Chuo-ku, Osaka, Japan, 540-0006
      • Osaka National Hospital
    • Higashiosaka, Osaka, Japan, 577-0818
      • Kinki University
    • Suita, Osaka, Japan, 565-0873
      • National Cerebral and Cardiovascular Center
  • Sendai
    • Aoba-ku, Sendai, Japan, 980-8574
      • Tohoku University Hospital
  • Shinjuku
    • Toyama, Shinjuku, Japan, 162-0052
      • National Center for Global Health and Medicine
  • Suita
    • Yamadaoka, Suita, Japan, 565-0871
      • Osaka University Hospital
  • Tokyo
    • Chuo, Tokyo, Japan, 104-8560
      • St. Luke's International Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BE1116; Single intravenous (I.V.) infusion, dosage depending on baseline INR and body weight	Biological: BE1116 (Prothrombin Complex Concentrate); Other Names: Beriplex® P/N; KcentraTM; Confidex®

What is the study measuring?

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
45-Day All-cause Mortality		Until Day 45
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
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

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Program Director, Acquired Bleeding, CSL Behring

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): March 1, 2016

Study Registration Dates

• First Submitted: October 27, 2014
• First Submitted That Met QC Criteria: October 31, 2014
• First Posted (ESTIMATE): November 2, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): May 4, 2016
• Last Update Submitted That Met QC Criteria: May 2, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Coagulation Disorders; Hemorrhage; Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: BE1116_3004