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.

Study Overview
=================
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.

Official Title
-----------------
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.

Conditions
-----------------
Significant Bleeding Risk

Intervention / Treatment
-----------------
* Drug: Octaplex
* Drug: Beriplex P/N (Kcentra)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Male or female patients at least 18 years of age. Patients currently on oral anticoagulation treatment with VKA of coumadin or warfarin type. 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; Patients with an international normalized ratio (INR) of 2.0 or above at the time of decision to reverse the anticoagulation status. 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 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). Patients for whom the planned surgery or procedure is commonly associated with a very low bleeding risk (e.g. catheter placement, gastroscopy). 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. Patients with a known congenital bleeding disorder. Patients with a known antiphospholipid antibody syndrome. Patients with present or past specific factor inhibitor activity. Patients with thrombocytopenia of <80,000/μL or history of heparin-induced thrombocytopenia. 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. Patients who have received prothrombin complex concentrates (PCCs), fresh frozen plasma or vitamin K within 72 hours prior to enrollment into the study. Patients with a known history of hypersensitivity to plasma-derived products. Patients with acute major bleeding or polytrauma. Pregnant or nursing women. Patients participating in another interventional clinical study currently or during the past 30 days prior to enrollment into this study. Patients previously enrolled in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octaplex<br>Participants to receive1 Octaplex infusion intravenously | Drug: Octaplex<br>* 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).<br>* Other names: 4 Factor Prothrombin Concentrate Complex;|
| Active Comparator: Beriplex P/N (Kcentra)<br>Participants to receive1 Kcentra infusions intravenously | Drug: Beriplex P/N (Kcentra)<br>* 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).<br>* Other names: Kcentra;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At the end of the surgery | 
| 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 | At the end of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measuring of International Normalized Ratio (INR) to ≤ 1.5 | 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. | 30 minutes after the end of infusion | 
| 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. | 30 minutes after the end of infusion | 
| Coagulation Factor VII Levels | 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. | 30 minutes after the end of infusion | 
| Coagulation Factor IX 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 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. | 30 minutes after the end of infusion | 
| Coagulation Factor X Levels | 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. | 30 minutes after the end of infusion | 
| Number of Patients Requiring Red Blood Cells (RBC) | Number of patients receiving red blood cells (RBC) during the surgery | At the end of surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
anticoagulant reversal, urgent surgery, invasive procedures, vitamin K, prothrombin complex concentrate, four-factor prothrombin complex concentrate (4F-PCC)