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 (BE1116_3003)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
CSL Behring
ClinicalTrials.gov Identifier:
NCT00803101
First received: December 4, 2008
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Reversal of Coagulopathy
Biological: Beriplex® P/N (Kcentra)
Biological: Fresh frozen plasma
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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 Vitamin K Antagonists in Subjects Requiring an Urgent Surgical Procedure

Resource links provided by NLM:


Further study details as provided by CSL Behring:

Primary Outcome Measures:
  • Percentage of Participants Achieving Hemostatic Efficacy During Surgery [ Time Frame: From the start of infusion until the end of surgery ] [ Designated as safety issue: No ]
    Hemostatic efficacy was rated as excellent, good, or poor/none, based on prespecified definitions. 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".

  • Percentage of Participants Who Had a Rapid Decrease of the INR [ Time Frame: 30 minutes after the end of infusion ] [ Designated as safety issue: No ]
    A rapid decrease of the INR was defined as an INR ≤ 1.3 at 30 minutes after the end of 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.


Secondary Outcome Measures:
  • Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S [ Time Frame: From pre-infusion until 24 h after the start of infusion ] [ Designated as safety issue: No ]
    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.

  • Transfusion of Packed Red Blood Cells (PRBCs) or Whole Blood [ Time Frame: From the start of surgery until 24 h after the start of surgery ] [ Designated as safety issue: No ]
    The total units of transfused PRBCs or whole blood

  • Percentage of Participants With INR Correction at Various Times After the Start of Infusion [ Time Frame: From the start of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Received Red Blood Cells [ Time Frame: From the start of surgery until 24 h after the start of surgery ] [ Designated as safety issue: No ]
    Red blood cells were PRBCs and whole blood

  • Overall Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
    Number of participants with TEAEs. TEAEs were defined as adverse events that developed or worsened following exposure to investigational medicinal product. Treatment-related TEAEs were events whose relationship to study treatment was related, probably related, or possibly related in the opinion of the investigator. Treatment emergent adverse events with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent serious adverse events (SAEs).


Enrollment: 176
Study Start Date: February 2009
Study Completion Date: February 2013
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Beriplex® P/N Biological: Beriplex® P/N (Kcentra)
Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body-weight.
Other Name: Kcentra
Active Comparator: Fresh frozen plasma Biological: Fresh frozen plasma
Intravenous infusion, dosage depending on baseline INR and body weight

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00803101

  Show 30 Study Locations
Sponsors and Collaborators
CSL Behring
Investigators
Study Director: Program Director, Clinical R&D CSL Behring
  More Information

Additional Information:
No publications provided

Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT00803101     History of Changes
Other Study ID Numbers: BE1116_3003, 1474, 2007-007862-39
Study First Received: December 4, 2008
Results First Received: January 12, 2014
Last Updated: March 11, 2014
Health Authority: United States: Food and Drug Administration
Russia: Ministry of Health of the Russian Federation
Armenia: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
Bulgaria: Bulgarian Drug Agency
Belarus: Ministry of Health
Romania: National Medicines Agency

Keywords provided by CSL Behring:
Anticoagulant reversal
Prothrombin Complex Concentrate
Coagulopathy
Coumarin derivatives
Emergency surgery
Invasive procedures
Vitamin K
Reversal of coagulopathy induced by coumarin derivatives
Kcentra

Additional relevant MeSH terms:
Blood Coagulation Disorders
Hemostatic Disorders
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders
Vitamin K
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014