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.

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).

Study Overview

• Status: Completed
• Conditions: Significant Bleeding Risk
• Intervention / Treatment: Drug: Octaplex; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Lesnoy, Belarus, 223040
    • Octapharma Research Site
  • Minsk, Belarus, 220024
    • Octapharma Research Site
  • Minsk, Belarus, 220032
    • Octapharma Research Site
  • Minsk, Belarus, 220040
    • Octapharma Research Site
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Octapharma Research Site
  • Ruse, Bulgaria, 7002
    • Octapharma Research Site
  • Sofia, Bulgaria, 1000
    • Octapharma Research Site
  • Sofia, Bulgaria, 1000
    • Octapharma Study Site
  • Varna, Bulgaria, 9010
    • Octapharma Research Site
• Georgia
  • Batumi, Georgia, 6010
    • Octapharma Research Site
  • Kutaisi, Georgia, 4600
    • Octapharma Research Site
  • Tbilisi, Georgia, 00114
    • Octapharma Research Site - Tbilisi
  • Tbilisi, Georgia, 00167
    • Octapharma Research Location - Tbilisi
  • Tbilisi, Georgia, 0141
    • Octapharma Research Site
  • Tbilisi, Georgia, 0159
    • Octapharma Research Location
  • Tbilisi, Georgia, 0159
    • Octapharma Research Site
  • Zugdidi, Georgia, 2100
    • Octapharma Research Site
• Germany
  • Berlin, Germany, 12559
    • Octapharma Research Site
  • Dresden, Germany, 01307
    • Octapharma Research Site
  • Frankfurt am Main, Germany, 60590
    • Octapharma Research Site
  • Heidelberg, Germany, 69120
    • Octapharma Research Site
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, 2004
    • Octapharma Research Site
• Poland
  • Bochnia, Poland, 32-700
    • Octapharma Research Site
  • Łódź, Poland, 95-513
    • Octapharma Research Site
• Romania
  • Bucharest, Romania, 010825
    • Octapharma Research Site
  • Bucharest, Romania, 020475
    • Octapharma Research Site
  • Cluj-Napoca, Romania, 400006
    • Octapharma Research Site
  • Craiova, Romania, 200624
    • Octapharma Research Site
  • Oradea, Romania, 410167
    • Octapharma Research Site
  • Timişoara, Romania, 3000723
    • Octapharma Research Site
• Russian Federation
  • Moscow, Russian Federation, 105203
    • Octapharma Research Site
  • Moscow, Russian Federation, 111539
    • Octapharma Research Site
  • Moscow, Russian Federation, 115446
    • Octapharma Research Site
  • Moscow, Russian Federation, 124489
    • Octapharma Research Site
  • Novosibirsk, Russian Federation, 630055
    • Octapharma Research Site
  • Omsk, Russian Federation, 644111
    • Octapharma Research Site
  • Saint Petersburg, Russian Federation, 192242
    • Octapharma Research Site
  • Saint Petersburg, Russian Federation, 194354
    • Octapharma Research Site
  • Saint Petersburg, Russian Federation, 197022
    • Octapharma Research Site
  • Saratov, Russian Federation, 410053
    • Regional Clinical Hospital
  • Smolensk, Russian Federation, 214019
    • Octapharma Research Site
  • Tver, Russian Federation, 170036
    • Octapharma Research Site
  • Yekaterinburg, Russian Federation, 620026
    • Octapharma Research Site
• Spain
  • Barcelona, Spain, 08907
    • Octapharma Research Site
  • Palma De Mallorca, Spain, 07120
    • Octapharma Research Site
  • Valencia, Spain, 46026
    • Octapharma Research Site
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Octapharma Research Site
  • Chernivtsi, Ukraine, 58001
    • Octapharma Research Site
  • Dnipro, Ukraine, 49005
    • Octapharma Research Location
  • Dnipro, Ukraine, 49005
    • Octapharma Research Site
  • Dnipro, Ukraine, 49102
    • Octapharma Research Site
  • Ivano-Frankivs'k, Ukraine, 76018
    • Octapharma Research Site
  • Kharkiv, Ukraine, 61037
    • Octapharma Research Site
  • Kharkiv, Ukraine, 61103
    • Octapharma Research Site
  • Kropyvnytskyi, Ukraine, 25006
    • Octapharma Research Site
  • Kyiv, Ukraine, 01133
    • Octapharma Research Site
  • L'viv, Ukraine, 79010
    • Octapharma Research Site
  • Luts'k, Ukraine, 43006
    • Octapharma Research Site
  • Lviv, Ukraine, 79034
    • Octapharma Research Site
  • Odesa, Ukraine, 65006
    • Octapharma Research Site
  • Vinnytsia, Ukraine, 21018
    • Octapharma Research Site
  • Vinnytsya, Ukraine, 21018
    • Octapharma Research Site
  • Zaporizhzhya, Ukraine, 69000
    • Octapharma Research Site
  • Zhytomyr, Ukraine, 12430
    • Octapharma Research Site
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Octapharma Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Octapharma Research Site
  • Florida
    • Miami, Florida, United States, 33136
      • Octapharma Research Site
    • Tampa, Florida, United States, 33606
      • Octapharma Research Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Octapharma Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Octapharma Research Site
  • New York
    • Rochester, New York, United States, 14642
      • Octapharma Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Octapharma Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • Octapharma Research Site
    • Columbus, Ohio, United States, 43210
      • Octapharma Research Site
    • Dayton, Ohio, United States, 45409
      • Octapharma Research Site
    • Fairborn, Ohio, United States, 45324
      • Octapharma Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Octapharma Research Site
    • Pittsburgh, Pennsylvania, United States, 15213
      • Octapharma Study Site
    • Pittsburgh, Pennsylvania, United States, 15219
      • Octapharma Research Site
    • Pittsburgh, Pennsylvania, United States, 15232
      • Octapharma Research Site
    • Pittsburgh, Pennsylvania, United States, 15237
      • Octapharma Research Site
  • Texas
    • Austin, Texas, United States, 78701
      • Octapharma Research Site (0115)
    • Austin, Texas, United States, 78701
      • Octapharma Research Site (0127)
    • Dallas, Texas, United States, 75390
      • Octapharma Research Site
    • Round Rock, Texas, United States, 78665
      • Octapharma Research Site
  • Washington
    • Puyallup, Washington, United States, 98374
      • Octapharma Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Octaplex; Participants to receive1 Octaplex infusion intravenously	Drug: 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).; Other Names: 4F PCC; 4 Factor PCC; 4 Factor Prothrombin Concentrate Complex
Active Comparator: Beriplex P/N (Kcentra); Participants to receive1 Kcentra infusions intravenously	Drug: 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).; Other Names: Kcentra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemostatic efficacy rating	Efficacy will be rated by the investigator at the end of the surgery in a blinded manner based on a 4-point hemostatic efficacy scale taking into account blood loss and transfusion requirements in the context of the surgery.	At the end of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correction 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 Levels	Change in coagulation factor levels from baseline to 30 (± 15 min) after the end of infusion: o Factor II	30 minutes after the end of infusion
Coagulation Factor Levels	Change in coagulation factor levels from baseline to 30 (± 15 min) after the end of infusion: o Factor VII	30 minutes after the end of infusion
Coagulation Factor Levels	Change in coagulation factor levels from baseline to 30 (± 15 min) after the end of infusion: o Factor IX	30 minutes after the end of infusion
Coagulation Factor Levels	Change in coagulation factor levels from baseline to 30 (± 15 min) after the end of infusion: o Factor X	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	through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: Octapharma
• Investigators: Study Director: Wolfgang Frenzel, International Medical Monitor

Publications and helpful links

General Publications

• American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006 Jul;105(1):198-208. doi: 10.1097/00000542-200607000-00030. No abstract available.
• Campbell P, Roberts G, Eaton V. Managing warfarin therapy in the community. Aust Prescriber 2001; 24:86-89.
• Cushman M, et al. Clinical Practice Guide on Antithrombotic Drug Dosing and Management of Antithrombotic Drug-Associated Bleeding Complications in Adults, American Society of Hematology, 2014.
• Gohlke-Barwolf C. [Anticoagulation in surgery, after hemorrhagic complications and in pregnancy]. Z Kardiol. 1998;87 Suppl 4:56-62. German.
• 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.
• Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error probability spending functions. Stat Med. 1990 Dec;9(12):1439-45. doi: 10.1002/sim.4780091207.
• Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M; British Committee for Standards in Haematology. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol. 2011 Aug;154(3):311-24. doi: 10.1111/j.1365-2141.2011.08753.x. Epub 2011 Jun 14. No abstract available.
• Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost. 2006 May;4(5):967-70. doi: 10.1111/j.1538-7836.2006.01815.x.
• Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997 Mar;77(3):477-80.
• Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ. 2002 Nov 9;325(7372):1073-5. doi: 10.1136/bmj.325.7372.1073.
• Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996 Aug 17;348(9025):423-8. doi: 10.1016/s0140-6736(96)01109-9.
• A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol. 1997 Dec;42(6):857-65. doi: 10.1002/ana.410420606.
• van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res. 2006;118(3):313-20. doi: 10.1016/j.thromres.2005.08.005. Epub 2005 Sep 21.
• Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res. 2002 Oct 1;108(1):25-30. doi: 10.1016/s0049-3848(02)00402-4.

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2017
• Primary Completion (Actual): February 23, 2022
• Study Completion (Actual): February 23, 2022

Study Registration Dates

• First Submitted: April 5, 2016
• First Submitted That Met QC Criteria: April 14, 2016
• First Posted (Estimate): April 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 12, 2022
• Last Update Submitted That Met QC Criteria: April 11, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: urgent surgery; prothrombin complex concentrate; vitamin K; anticoagulant reversal; invasive procedures; four-factor prothrombin complex concentrate (4F-PCC)
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Hemostatics; Coagulants; Thrombin; Protein C; Protein S
• Other Study ID Numbers: LEX-209

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No