Clinical trial NCT00803101: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Reversal of Coagulopathy
Keywords: Anticoagulant reversal
Prothrombin Complex Concentrate
Coagulopathy
Coumarin derivatives
Emergency surgery
Invasive procedures
Vitamin K
Reversal of coagulopathy induced by coumarin derivatives
Kcentra
Lead sponsor: CSL Behring
Sponsor class: INDUSTRY
First posted: 2008-12-05
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants Achieving Hemostatic Efficacy During Surgery
timeFrame: From the start of infusion until the end of surgery
measure: Percentage of Participants Who Had a Rapid Decrease of the INR
timeFrame: 30 minutes after the end of infusion
Secondary outcomes:
measure: Plasma Levels of Factors II, VII, IX, and X, Protein C, and Protein S
timeFrame: From pre-infusion until 24 h after the start of infusion
measure: Transfusion of Packed Red Blood Cells (PRBCs) or Whole Blood
timeFrame: From the start of surgery until 24 h after the start of surgery
measure: Percentage of Participants With INR Correction at Various Times After the Start of Infusion
timeFrame: From the start of infusion until INR correction; calculated at 0.5, 1, 3, 6, 12, and 24 h after the start of infusion
measure: Percentage of Participants Who Received Red Blood Cells
timeFrame: From the start of surgery until 24 h after the start of surgery
measure: Overall Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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
Other outcomes:
Locations:
city: Newark
country: United States
facility: Study Site
state: Delaware
city: Lexington
country: United States
facility: Study site
state: Kentucky
city: Boston
country: United States
facility: Study Site
state: Massachusetts
city: Duluth
country: United States
facility: Study Site
state: Minnesota
city: Minneapolis
country: United States
facility: Study Site
state: Minnesota
city: Albuquerque
country: United States
facility: Study Site
state: New Mexico
city: Rochester
country: United States
facility: Study Site
state: New York
city: Winston-Salem
country: United States
facility: Study Site
state: North Carolina
city: Philadelphia
country: United States
facility: Study Site
state: Pennsylvania
city: West Reading
country: United States
facility: Study Site
state: Pennsylvania
city: Wilkes Barre
country: United States
facility: Study Site
state: Pennsylvania
city: Memphis
country: United States
facility: Study Site
state: Tennessee
city: Austin
country: United States
facility: Study Site
state: Texas
city: Bryan
country: United States
facility: Study site
state: Texas
city: El Paso
country: United States
facility: Study Site
state: Texas
city: Houston
country: United States
facility: Study Site
state: Texas
city: Minsk
country: Belarus
facility: Study Site 1
city: Minsk
country: Belarus
facility: Study Site 2
city: Rousse
country: Bulgaria
facility: Study Site
city: Sofia
country: Bulgaria
facility: Study Site 4
city: Varna
country: Bulgaria
facility: Study Site
city: Beirut
country: Lebanon
facility: Study Site
city: Saida
country: Lebanon
facility: Study Site
city: Timisoara
country: Romania
facility: Study Site
city: Barnaul
country: Russian Federation
facility: Study Site 2
city: Kazan
country: Russian Federation
facility: Study Site
city: Moscow
country: Russian Federation
facility: Study Site 1
city: Moscow
country: Russian Federation
facility: Study Site 2
city: Novosibirsk
country: Russian Federation
facility: Study Site
city: Saint Petersburg
country: Russian Federation
facility: Study Site
Study officials:
affiliation: CSL Behring
name: Program Director, Clinical R&D
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.