Reversal of CoagulopathyPhase 3BE1116_3003NCT00803101
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
A Phase 3 study testing Beriplex® P/N (Kcentra) and Fresh frozen plasma in people with Reversal of Coagulopathy, run by CSL Behring at 30 sites in 6 countries.
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 vitamin K antagonists in subjects who require immediate correction of international normalized ratio (INR) because of emergency surgery. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Reversal of Coagulopathy
- What is being tested?
- Beriplex® P/N (Kcentra) and Fresh frozen plasma
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 176 participants
- Where
- 30 sitesin 6 countries
- Study dates
- Feb 2009to Feb 2013
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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),
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- 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
Trial locations and contacts
30 sites in 6 countries.
30 sites in 6 countries
United States16 sites
Study Site
Albuquerque, New Mexico, 87131
Study Site
Austin, Texas, 78701
Study Site
Boston, Massachusetts, 02114
Study site
Bryan, Texas, 77802
Study Site
Duluth, Minnesota, 55805
Study Site
El Paso, Texas, 79905
Study Site
Houston, Texas, 77030
Study site
Lexington, Kentucky, 40536
Study Site
Memphis, Tennessee, 38163
Study Site
Minneapolis, Minnesota, 55415
Study Site
Newark, Delaware, 19718
Study Site
Philadelphia, Pennsylvania, 19107
Study Site
Rochester, New York, 14642
Study Site
West Reading, Pennsylvania, 19611
Study Site
Wilkes-Barre, Pennsylvania, 18711
Study Site
Winston-Salem, North Carolina, 27157
Russia6 sites
Study Site 2
Barnaul, 656038
Study Site
Kazan', 420012
Study Site 1
Moscow, 105203
Study Site 2
Moscow, 125206
Study Site
Novosibirsk, 630051
Study Site
Saint Petersburg, 192242
Bulgaria3 sites
Study Site
Rousse, 7002
Study Site 4
Sofia, 1606
Study Site
Varna, 9010
About this study
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
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.
- Conditions
- Reversal of Coagulopathy
- Being tested
- Beriplex® P/N (Kcentra), Fresh frozen plasma
- Keywords
- Anticoagulant reversal, Prothrombin Complex Concentrate, Coagulopathy, Coumarin derivatives, Emergency surgery, Invasive procedures, Vitamin K, Reversal of coagulopathy induced by coumarin derivatives, Kcentra
- Medical subject headings
- Hemophilia B, Hemostatic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Beriplex® P/N (Kcentra)Biological
Also called Kcentra
Intravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body-weight.
Fresh frozen plasmaBiological
Intravenous infusion, dosage depending on baseline INR and body weight
| Study group | Role | What they receive |
|---|---|---|
| Beriplex® P/N | Experimental | Not described Receives: Biological: Beriplex® P/N (Kcentra) |
| Fresh frozen plasma | Active comparator | Not described Receives: Biological: Fresh frozen plasma |
What is being measured
The primary outcome is the main question the study is designed to answer.
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".
Measured: 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.
Measured: 30 minutes after the end of infusion
Secondary outcomes (5)
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.
Measured: 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
Measured: 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.
Measured: 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
Measured: 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).
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2008 (estimated)
- Study startFeb 2009
- Primary completionNov 2012
- Study completionFeb 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Reversal of CoagulopathyStudies of the same condition, open and under way.
- More trials run by CSL BehringThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 176 participants (actual)
Sponsor and investigators
- Lead sponsor
- CSL Behring
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Program Director, Clinical R&D, Study director, CSL Behring
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00803101
- Sponsor's protocol ID
- BE1116_3003
- Other IDs
- 1474, 2007-007862-39
- Acronym
- BE1116_3003
- Status last verified
- Mar 2014
- First submitted
- 4 Dec 2008
- Last updated
- 6 Apr 2015
- Results posted
- Yes, on ClinicalTrials.gov
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.
PubMed 25728933Kincaid M, Young AJ, Dybdahl D, Taylor BC. Effectiveness of Four-Factor Prothrombin Complex Concentrate Versus Plasma in Patients on Vitamin K Antagonists Undergoing Urgent Orthopedic Surgery: A Post Hoc Analysis. Adv Ther. 2026 Jun;43(6):2783-2794. doi: 10.1007/s12325-026-03561-z. Epub 2026 Mar 30.
PubMed 41910938Refaai 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.
PubMed 26135740
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00803101
- Acronym / sponsor ID
- BE1116_3003 / BE1116_3003
- 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
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 176 participants (actual)
- Lead sponsor
- CSL BehringIndustry (pharma, biotech, devices)
- Study start
- Feb 2009
- Primary completion
- Nov 2012 (actual)
- Study completion
- Feb 2013 (actual)
- First posted
- 5 Dec 2008 (estimated)
- Results
- Posted 25 Feb 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Beriplex® P/N | Experimental | Biological: Beriplex® P/N (Kcentra) |
| Fresh frozen plasma | Active comparator | Biological: Fresh frozen plasma |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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,
Key exclusion criteria (30 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Beriplex® P/N (Kcentra)Also: KcentraIntravenous infusion, dosage depending on baseline INR, amount of coagulation factor IX and body-weight. | Biological | Beriplex® P/N |
| Fresh frozen plasmaIntravenous infusion, dosage depending on baseline INR and body weight | Biological | Fresh frozen plasma |
Primary outcome
Percentage of Participants Achieving Hemostatic Efficacy During Surgery
Time frame: From the start of infusion until the end of 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".
Percentage of Participants Who Had a Rapid Decrease of the INR
Time frame: 30 minutes after the end of infusion
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.
5 secondary outcomes
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
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
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
Percentage of Participants Who Received Red Blood Cells
Time frame: From the start of surgery until 24 h after the start of surgery
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 25728933Goldstein 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.
- Derived from this study: PubMed 41910938Kincaid M, Young AJ, Dybdahl D, Taylor BC. Effectiveness of Four-Factor Prothrombin Complex Concentrate Versus Plasma in Patients on Vitamin K Antagonists Undergoing Urgent Orthopedic Surgery: A Post Hoc Analysis. Adv Ther. 2026 Jun;43(6):2783-2794. doi: 10.1007/s12325-026-03561-z. Epub 2026 Mar 30.
- Derived from this study: PubMed 26135740Refaai 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Program Director, Clinical R&D study director
CSL Behring
30 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Beriplex® P/N (Kcentra) and Fresh frozen plasma in people with Reversal of Coagulopathy, run by CSL Behring at 30 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Apr 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in United States, Russia, Bulgaria, Belarus, Lebanon and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants Achieving Hemostatic Efficacy During Surgery (time frame: From the start of infusion until the end of surgery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00803101, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2015.