Study of Octaplex, a Four-factor Prothrombin Complex Concentrate (4F-PCC) and Beriplex® P/N (Kcentra) for the Reversal of Vitamin K Antagonist (VKA) Induced Anticoagulation in Patients Needing Urgent Surgery With Significant Bleeding Risk.

A Phase III, Randomized, Double-blind, Multicenter Study to Assess the Efficacy and Safety of OCTAPLEX, a Four-factor Prothrombin Complex Concentrate (4F-PCC), Compared to the 4F-PCC Beriplex® P/N (Kcentra), for the Reversal of Vitamin K Antagonist (VKA) Induced Anticoagulation in Patients Needing Urgent Surgery With Significant Bleeding Risk.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02740335

Enrollment

208

Registered

2016-04-15

Start date

2017-06-08

Completion date

2022-02-23

Last updated

2023-03-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Significant Bleeding Risk

Keywords

anticoagulant reversal, urgent surgery, invasive procedures, vitamin K, prothrombin complex concentrate, four-factor prothrombin complex concentrate (4F-PCC)

Brief summary

To demonstrate that the efficacy of OCTAPLEX as a reversal agent in patients under Vitamin K Antagonist (VKA) therapy with the need for urgent surgery with significant bleeding risk is clinically non-inferior to that Beriplex® P/N (Kcentra).

Detailed description

The primary objective of the study is to demonstrate that the efficacy of OCTAPLEX as a reversal agent in patients under Vitami n K Antagonist (VKA)therapy with the need for urgent surgery with significant bleeding risk is clinically non-inferior to that Beriplex® P/N (Kcentra). The secondary objective of the study is to investigate the safety and tolerability of OCTAPLEX compared to Beriplex® P/N (Kcentra) in patients under Vitamin K Antagonist (VKA) therapy with the need for urgent surgery with significant bleeding risk.

Interventions

DRUGOctaplex

OCTAPLEX will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\ 3 units/kg/min), up to a maximum rate of 8.4 mL/min (\ 210 units/min).

DRUGBeriplex P/N (Kcentra)

Beriplex® P/N (Kcentra) will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\ 3 units/kg/min), up to a maximum rate of 8.4 mL/min (\ 210 units/min).

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Male or female patients at least 18 years of age. 2. Patients currently on oral anticoagulation treatment with VKA of coumadin or warfarin type. 3. Patients being admitted to the hospital or currently hospitalized where: * an urgent surgery carrying significant bleeding risk (≥50 mL expected blood loss) is required as part of routine clinical care; * the use of oral or parenteral vitamin K alone to reverse anticoagulation is deemed too slow or inappropriate for reversal; 4. Patients with an international normalized ratio (INR) of 2.0 or above at the time of decision to reverse the anticoagulation status. 5. Patients who have given written informed consent and who are able and willing to comply with the procedures described in the study protocol.

Exclusion criteria

1. Patients with a life expectancy of less than 48 hours per physician's judgment (e.g. patients with a Glasgow Coma Scale equal to 3 or a Head Abbreviated Injury Score of 6, patients requiring continuous inotropic or pressor support, and patients whose status is post cardiac arrest). 2. Patients for whom the planned surgery or procedure is commonly associated with a very low bleeding risk (e.g. catheter placement, gastroscopy). 3. Patients with a history of thromboembolic events (TEEs), myocardial infarction, unstable angina pectoris, critical aortic stenosis, cerebrovascular accident, transient ischemic attack, severe peripheral vascular disease, or disseminated intravascular coagulation within 3 months of enrollment. 4. Patients with a known congenital bleeding disorder. 5. Patients with a known antiphospholipid antibody syndrome. 6. Patients with present or past specific factor inhibitor activity. 7. Patients with thrombocytopenia of \<80,000/μL or history of heparin-induced thrombocytopenia. 8. Patients who have received heparin of any type or any non-VKA anticoagulant within 24 hours prior to enrollment into the study or with potential need to receive these medications before completion of hemostasis evaluation at the end of surgery. 9. Patients who have received prothrombin complex concentrates (PCCs), fresh frozen plasma or vitamin K within 72 hours prior to enrollment into the study. 10. Patients with a known history of hypersensitivity to plasma-derived products. 11. Patients with acute major bleeding or polytrauma. 12. Pregnant or nursing women. 13. Patients participating in another interventional clinical study currently or during the past 30 days prior to enrollment into this study. 14. Patients previously enrolled in this study.

Design outcomes

Primary

Measure	Time frame	Description
Hemostatic Efficacy Rating by IEAB	At the end of the surgery	Hemostatic Efficacy rated by the Independent Endpoint Adjudication Committee based on a 1 to 4 point hemostatic efficacy scale, taking into account blood loss and transfusion requirements in the context of the surgery. Hemostatic efficacy was assessed based on objective criteria in the categories 'excellent', 'good', 'moderate', or 'none'. Ratings of 'excellent' and 'good' were considered as 'effective' hemostasis, while ratings of 'moderate' and 'none' were considered as 'ineffective' hemostasis.
Dichotomous Hemostasis Success	At the end of surgery	To demostrate clinical non-inferiority of treatment with Octaplex to treatment with Beriplex P/N (Kcentra) with respect to hemostatic success. Effective hemostatis includes Excellent and Good ratings, while Ineffective hemostasis includes Moderate, None and missing ratings from Global hemostatic efficacy observed by IEAB

Secondary

Measure	Time frame	Description
Coagulation Factor VII Levels	30 minutes after the end of infusion	Change in coagulation factor levels from baseline to after the end of infusion using the Hodges-Lehmann Estimator for median differences: o Factor VII The Hodges-Lehmann Estimator is a method of robust estimation. This estimator is used to give an estimate of the difference between the values in two sets of data. If the two sets of data contain m and n data points respectively, m × n pairs of points (one from each set) can be formed and each pair gives a difference of values. The Hodges-Lehmann estimator for the difference is defined as the median of the m × n differences.
Coagulation Factor IX Levels	30 minutes after the end of infusion	Change in coagulation factor levels from baseline to after the end of infusion using the Hodges-Lehmann Estimator for median differences: o Factor II Factor IX The Hodges-Lehmann Estimator is a method of robust estimation. This estimator is used to give an estimate of the difference between the values in two sets of data. If the two sets of data contain m and n data points respectively, m × n pairs of points (one from each set) can be formed and each pair gives a difference of values. The Hodges-Lehmann estimator for the difference is defined as the median of the m × n differences.
Measuring of International Normalized Ratio (INR) to ≤ 1.5	30 minutes after the end of infusion	Number of patients with an international normalized ratio (INR) value of less or equal to 1.5 at 30 min (± 15 min) after the end of infusion.
Number of Patients Requiring Red Blood Cells (RBC)	At the end of surgery	Number of patients receiving red blood cells (RBC) during the surgery
Coagulation Factor X Levels	30 minutes after the end of infusion	Change in coagulation factor levels from baseline to after the end of infusion using the Hodges-Lehmann Estimator for median differences: o Factor X The Hodges-Lehmann Estimator is a method of robust estimation. This estimator is used to give an estimate of the difference between the values in two sets of data. If the two sets of data contain m and n data points respectively, m × n pairs of points (one from each set) can be formed and each pair gives a difference of values. The Hodges-Lehmann estimator for the difference is defined as the median of the m × n differences.
Coagulation Factor II Levels	30 minutes after the end of infusion	Change in coagulation factor levels from baseline to after the end of infusion using the Hodges-Lehmann Estimator for median differences: o Factor II The Hodges-Lehmann Estimator is a method of robust estimation. This estimator is used to give an estimate of the difference between the values in two sets of data. If the two sets of data contain m and n data points respectively, m × n pairs of points (one from each set) can be formed and each pair gives a difference of values. The Hodges-Lehmann estimator for the difference is defined as the median of the m × n differences.

Countries

Belarus, Bulgaria, Georgia, Germany, Moldova, Poland, Romania, Russia, Spain, Ukraine, United States

Participant flow

Participants by arm

Arm	Count
Octaplex Participants to receive1 Octaplex infusion intravenously Octaplex: OCTAPLEX will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\ 3 units/kg/min), up to a maximum rate of 8.4 mL/min (\ 210 units/min).	105
Beriplex P/N (Kcentra) Participants to receive 1 Kcentra infusion intravenously Beriplex P/N (Kcentra): Beriplex® P/N (Kcentra) will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\ 3 units/kg/min), up to a maximum rate of 8.4 mL/min (\ 210 units/min).	103
Total	208

Baseline characteristics

Characteristic	Beriplex P/N (Kcentra)	Total	Octaplex
Age, Continuous	66.8 Years	66.2 Years	65.6 Years
Estimated Average Blood Loss ≥100 mL but <200 mL	25 participants	51 participants	26 participants
Estimated Average Blood Loss ≥200 mL	50 participants	105 participants	55 participants
Estimated Average Blood Loss ≥50mL but <100 mL	28 participants	52 participants	24 participants
History of TEE Absence of Embolic or Thrombotic Event	85 participants	177 participants	92 participants
History of TEE Presence of Embolic or Thrombotic Event	18 participants	31 participants	13 participants
Pre-Infusion Anticoagulation Therapy Sol. Fraxiparine (nadroparin calcium)	0 participants	1 participants	1 participants
Pre-Infusion Anticoagulation Therapy Vitamin K Antagonist	103 participants	208 participants	105 participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	102 Participants	207 Participants	105 Participants
Sex: Female, Male Female	43 Participants	90 Participants	47 Participants
Sex: Female, Male Male	60 Participants	118 Participants	58 Participants
Type of Surgey Cardiothoracic Surgery	4 participants	9 participants	5 participants
Type of Surgey Orthopaedic Surgery	5 participants	12 participants	7 participants
Type of Surgey Other Surgery Type	94 participants	187 participants	93 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	5 / 105	1 / 103
other Total, other adverse events	86 / 105	80 / 103
serious Total, serious adverse events	13 / 105	6 / 103

Outcome results

Primary

Dichotomous Hemostasis Success

To demostrate clinical non-inferiority of treatment with Octaplex to treatment with Beriplex P/N (Kcentra) with respect to hemostatic success. Effective hemostatis includes Excellent and Good ratings, while Ineffective hemostasis includes Moderate, None and missing ratings from Global hemostatic efficacy observed by IEAB

Time frame: At the end of surgery

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Octaplex	Dichotomous Hemostasis Success	Effective	99 Participants
Octaplex	Dichotomous Hemostasis Success	Ineffective	6 Participants
Beriplex P/N (Kcentra)	Dichotomous Hemostasis Success	Effective	97 Participants
Beriplex P/N (Kcentra)	Dichotomous Hemostasis Success	Ineffective	6 Participants

Primary

Hemostatic Efficacy Rating by IEAB

Hemostatic Efficacy rated by the Independent Endpoint Adjudication Committee based on a 1 to 4 point hemostatic efficacy scale, taking into account blood loss and transfusion requirements in the context of the surgery. Hemostatic efficacy was assessed based on objective criteria in the categories 'excellent', 'good', 'moderate', or 'none'. Ratings of 'excellent' and 'good' were considered as 'effective' hemostasis, while ratings of 'moderate' and 'none' were considered as 'ineffective' hemostasis.

Time frame: At the end of the surgery

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Octaplex	Hemostatic Efficacy Rating by IEAB	Excellent - 4	41 Participants
Octaplex	Hemostatic Efficacy Rating by IEAB	Good - 3	58 Participants
Octaplex	Hemostatic Efficacy Rating by IEAB	Moderate - 2	6 Participants
Octaplex	Hemostatic Efficacy Rating by IEAB	None - 1	0 Participants
Octaplex	Hemostatic Efficacy Rating by IEAB	Effective	99 Participants
Octaplex	Hemostatic Efficacy Rating by IEAB	Ineffective	6 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	Effective	97 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	Excellent - 4	50 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	None - 1	0 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	Good - 3	47 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	Ineffective	6 Participants
Beriplex P/N (Kcentra)	Hemostatic Efficacy Rating by IEAB	Moderate - 2	6 Participants

Secondary

Coagulation Factor II Levels

Change in coagulation factor levels from baseline to after the end of infusion using the Hodges-Lehmann Estimator for median differences: o Factor II The Hodges-Lehmann Estimator is a method of robust estimation. This estimator is used to give an estimate of the difference between the values in two sets of data. If the two sets of data contain m and n data points respectively, m × n pairs of points (one from each set) can be formed and each pair gives a difference of values. The Hodges-Lehmann estimator for the difference is defined as the median of the m × n differences.