Efficacy and Safety Study of BERIPLEX® P/N (Kcentra) Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy

Blood Coagulation Disorders Clinical Trial

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 Coumarin Derivatives in Subjects With Acute Major Bleeding

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00708435
• Other study ID #: BE1116_3002
• Secondary ID: 14622007-007861-
• Status: Completed
• Phase: Phase 3
• First received: July 1, 2008
• Last updated: January 1, 2014
• Start date: June 2008
• Est. completion date: November 2010

Study information

• Verified date: September 2013
• Source: CSL Behring
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBulgaria: Bulgarian Drug AgencyUkraine: State Pharmacological Center - Ministry of HealthArmenia: Ministry of HealthRussia: Ministry of Health of the Russian FederationBelarus: Ministry of HealthRomania: National Medicines Agency
• Study type: Interventional

Clinical Trial 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 coumarin derivatives in subjects who require immediate correction of INR (International Normalized Ratio)and to stop an acute major bleeding.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 216
• Est. completion date: November 2010
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female subjects = 18 years

• Subjects who have received oral vitamin K-antagonist therapy

• Subjects who have acute major bleeding, defined as one of the following:

life-threatening or potentially life-threatening, acute bleeding associated with a fall in hemoglobin (Hb) level = 2g/dL, bleeding requiring blood product transfusion

• INR = 2 within 3 hours before start of study treatment

• Informed consent has been obtained

Exclusion Criteria:

• Expected survival of less than 3 days, or expected surgery in less than 1 day

• Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control the acute bleeding event

• Use of unfractionated or low molecular weight heparin use from 24 hours prior to enrollment or expected need within 24 hours after start of infusion

• For patients with ICH: Glasgow coma score (GCS) < 7; intracerebral hematoma volume > 30cc as assessed by ABC/21; for subdural hematomas: maximum thickness = 10 mm, midline shift = 5 mm; for subarachnoid hemorrhage: any evidence of hydrocephalus; infratentorial ICH location; epidural hematomas; intraventricular extension of hemorrhage; modified Rankin score (mRS) of >3 prior to ICH

• History of thrombotic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within 3 months of enrollment

• Known history of antiphospholipid antibody syndrome or lupus anticoagulant antibodies

• Suspected or confirmed sepsis at time of enrollment

• Administration of whole blood, plasma, plasma fractions or platelets within 2 weeks prior to inclusion into the study

• Large blood vessel rupture (e.g. in advanced cancer patient)

• 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Major Bleeding
• Blood Coagulation Disorders
• Hemorrhage
• Hemostatic Disorders

Intervention

Biological:
• Beriplex® P/N (Kcentra)
Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body weight
• Fresh frozen plasma
Intravenous Infusion, dosage depending on baseline INR and body weight

Locations

Country	Name	City	State
Belarus	Study Site 1	Minsk
Belarus	Study Site 2	Minsk
Bulgaria	Study Site	Pleven
Bulgaria	Study Site	Plovdiv
Bulgaria	Study Site	Rousse
Bulgaria	Study Site 1	Sofia
Bulgaria	Study Site 2	Sofia
Bulgaria	Study Site 3	Sofia
Bulgaria	Study Site 4	Sofia
Romania	Study Site	Brasov
Romania	Study Site 1	Bucharest
Romania	Study Site 2	Bucharest
Romania	Study Site 3	Bucharest
Romania	Study Site	Cluj-Napoca
Romania	Study Site	Timisoara
Russian Federation	Study Site	Arkhangelsk
Russian Federation	Study Site 1	Barnaul
Russian Federation	Study Site 2	Barnaul
Russian Federation	Study Site	Kazan
Russian Federation	Study Site	Kemerovo
Russian Federation	Study Site 1	Moscow
Russian Federation	Study Site 2	Moscow
Russian Federation	Study Site 1	Nizhny Novgorod
Russian Federation	Study Site 2	Nizhny Novgorod
Russian Federation	Study Site 1	St. Petersburg
Russian Federation	Study Site 2	St. Petersburg
Ukraine	Study Site	Kharkov
Ukraine	Study Site	Vinnytsa
United States	Study Site	Albany	New York
United States	Study Site	Albuquerque	New Mexico
United States	Study Site	Allentown	Pennsylvania
United States	Study Site	Ann Arbor	Michigan
United States	Study Site	Austin	Texas
United States	Study Site	Baltimore	Maryland
United States	Study Site	Baltimore	Maryland
United States	Study Site	Birmingham	Alabama
United States	Study Site	Boston	Massachusetts
United States	Study Site	Charlottesville	Virginia
United States	Study Site	Chicago	Illinois
United States	Study Site	Duluth	Minnesota
United States	Study Site	Durham	North Carolina
United States	Study Site	El Paso	Texas
United States	Study Site	Hazard	Kentucky
United States	Study Site	Hershey	Pennsylvania
United States	Study Site	Houston	Texas
United States	Study Site 2	Houston	Texas
United States	Study Site	Jackson	Mississippi
United States	Study Site	Johnson City	New York
United States	Study Site	Los Angeles	California
United States	Study Site	Minneapolis	Minnesota
United States	Study Site	New York	New York
United States	Study Site	New York	New York
United States	Study Site	New York	New York
United States	Study Site	Newark	Delaware
United States	Study Site	Oak Park	Illinois
United States	Study Site	Orlando	Florida
United States	Study Site	Philadelphia	Pennsylvania
United States	Study Site	Philadelphia	Pennsylvania
United States	Study Site	Richmond	Virginia
United States	Study Site	Rochester	New York
United States	Study Site	Royal Oak	Michigan
United States	Study Site	Salt Lake City	Utah
United States	Study Site	San Franciso	California
United States	Study Site	St. Louis	Missouri
United States	Study Site	Staten Island	New York
United States	Study Site	Tampa	Florida
United States	Study Site	Temple	Texas
United States	Study Site	West Reading	Pennsylvania
United States	Study Site	Worchester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
CSL Behring

Countries where clinical trial is conducted

United States,  Belarus,  Bulgaria,  Romania,  Russian Federation,  Ukraine, 

References & Publications (1)

Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, pha — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving Hemostatic Efficacy of Stopping an Ongoing Major Bleed	Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 1 and 4 hours after the end of infusion. 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".	At 1 and 4 hours after the end of infusion	No
Primary	Percentage of Participants Who Had a Rapid Decrease of the International Normalized Ratio (INR)	A rapid decrease of the international normalized ratio (INR) was defined as an INR = 1.3 at 30 minutes after the end of the 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 end of infusion	No
Secondary	Percentage of Participants Who Had Hemostatic Efficacy for Visible or Non-visible Musculoskeletal Bleeding	Hemostatic efficacy was determined by a blinded independent board as excellent, good, or poor/none, based on prespecified definitions. Assessments of visible or non-visible musculoskeletal bleeding were made at 3 and 6 hours after the start of infusion. 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".	At 3 and 6 hours after the start of infusion	No
Secondary	Incremental in Vivo Recovery (IVR) (Response) of Factors II, VII, IX, and X, Protein C, and Protein S for Beriplex	The incremental IVR [(IU/dL)/(IU/kg)] was 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	No
Secondary	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 preinfusion until 24 h after the start of infusion	No
Secondary	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.	No
Secondary	Percentage of Participants With INR Correction at Various Times After Randomization	The time taken from randomization to INR correction (defined as an INR = 1.3) was recorded. The percentage of participants with INR correction was calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization.	From randomization until INR correction; calculated at 2.5, 3, 5, 8, 14, and 26 h after randomization.	No
Secondary	Transfusion of Red Blood Cells	Red blood cells were packed red blood cells (PRBCs).	From the start of infusion until 24 h after the start of infusion	No
Secondary	Use of 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	No
Secondary	45-Day All-cause Mortality		Until Day 45	No
Secondary	Overall Treatment-emergent Adverse Events (TEAEs)	Number of participants with TEAEs. Treatment-related AEs were defined as events whose relationship to study treatment was definitely related, probably related, or possibly related in the opinion of the investigator. AEs with missing relationship were considered related to treatment. Serious TEAEs were treatment-emergent SAEs. Deaths reported up to and including Day 45; one additional Beriplex death occurred after Day 45.	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.	Yes

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