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)

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

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.

Study Overview

• Status: Completed
• Conditions: Reversal of Coagulopathy
• Intervention / Treatment: Biological: Beriplex® P/N (Kcentra); Biological: Fresh frozen plasma

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Minsk, Belarus
    • Study Site 1
  • Minsk, Belarus
    • Study Site 2
• Bulgaria
  • Rousse, Bulgaria, 7002
    • Study Site
  • Sofia, Bulgaria, 1606
    • Study Site 4
  • Varna, Bulgaria, 9010
    • Study Site
• Lebanon
  • Beirut, Lebanon, 2833-7401
    • Study Site
  • Saida, Lebanon, 652
    • Study Site
• Romania
  • Timisoara, Romania, 300736
    • Study Site
• Russian Federation
  • Barnaul, Russian Federation, 656038
    • Study Site 2
  • Kazan, Russian Federation, 420012
    • Study Site
  • Moscow, Russian Federation, 105203
    • Study Site 1
  • Moscow, Russian Federation, 125206
    • Study Site 2
  • Novosibirsk, Russian Federation, 630051
    • Study Site
  • Saint Petersburg, Russian Federation, 192242
    • Study Site
• United States
  • Delaware
    • Newark, Delaware, United States, 19718
      • Study Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Study Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Study Site
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Study Site
    • Minneapolis, Minnesota, United States, 55415
      • Study Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Study Site
  • New York
    • Rochester, New York, United States, 14642
      • Study Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Study Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Study Site
    • West Reading, Pennsylvania, United States, 19611
      • Study Site
    • Wilkes Barre, Pennsylvania, United States, 18711
      • Study Site
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • Study Site
  • Texas
    • Austin, Texas, United States, 78701
      • Study Site
    • Bryan, Texas, United States, 77802
      • Study Site
    • El Paso, Texas, United States, 79905
      • Study Site
    • Houston, Texas, United States, 77030
      • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Kcentra
ACTIVE_COMPARATOR: Fresh frozen plasma	Biological: Fresh frozen plasma; Intravenous infusion, dosage depending on baseline INR and body weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Hemostatic Efficacy During Surgery	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".	From the start of infusion until the end of surgery
Percentage of Participants Who Had a Rapid Decrease of the INR	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.	30 minutes after the end of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 pre-infusion until 24 h after the start of infusion
Transfusion of Packed Red Blood Cells (PRBCs) or Whole Blood	The total units of transfused PRBCs or whole blood	From the start of surgery until 24 h after the start of surgery
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 Who Received Red Blood Cells	Red blood cells were PRBCs and whole blood	From the start of surgery until 24 h after the start of surgery
Overall Treatment-emergent Adverse Events (TEAEs)	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).	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

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• Goldstein JN, Refaai MA, Milling TJ Jr, Lewis B, Goldberg-Alberts R, Hug BA, Sarode R. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015 May 23;385(9982):2077-87. doi: 10.1016/S0140-6736(14)61685-8. Epub 2015 Feb 27.
• Refaai MA, Goldstein JN, Lee ML, Durn BL, Milling TJ Jr, Sarode R. Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal. Transfusion. 2015 Nov;55(11):2722-9. doi: 10.1111/trf.13191. Epub 2015 Jul 1.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): February 1, 2013

Study Registration Dates

• First Submitted: December 4, 2008
• First Submitted That Met QC Criteria: December 4, 2008
• First Posted (ESTIMATE): December 5, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 6, 2015
• Last Update Submitted That Met QC Criteria: March 18, 2015
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: Emergency surgery; Prothrombin Complex Concentrate; Invasive procedures; Coagulopathy; Vitamin K; Anticoagulant reversal; Kcentra; Coumarin derivatives; Reversal of coagulopathy induced by coumarin derivatives
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Coagulation Disorders; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Protein C; Protein S
• Other Study ID Numbers: BE1116_3003; 1474 (CSL Behring); 2007-007862-39 (EUDRACT_NUMBER)