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.

NCT02740335 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: LEX-209
• Study Type: interventional
• Target: 208
• Locations: 11 countries
• Sites: 86

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).

Conditions

Significant Bleeding Risk

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Measuring of International Normalized Ratio (INR) to ≤ 1.5

  30 minutes after the end of infusion

• Coagulation Factor II Levels

  30 minutes after the end of infusion

• Coagulation Factor VII Levels

  30 minutes after the end of infusion

• Coagulation Factor IX Levels

  30 minutes after the end of infusion

• Coagulation Factor X Levels

  30 minutes after the end of infusion

Study Arms (2)

Octaplex

EXPERIMENTAL

Participants to receive1 Octaplex infusion intravenously

Drug: Octaplex

Beriplex P/N (Kcentra)

ACTIVE COMPARATOR

Participants to receive1 Kcentra infusions intravenously

Drug: Beriplex P/N (Kcentra)

Interventions

Octaplex DRUG

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).

Also known as: 4F PCC, 4 Factor PCC, 4 Factor Prothrombin Concentrate Complex

Octaplex

Beriplex P/N (Kcentra) DRUG

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).

Also known as: Kcentra

Beriplex P/N (Kcentra)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Octapharma: lead

Study Sites (86)

Octapharma Research Site

Aurora, Colorado, 80045, United States

Location

Octapharma Research Site

New Haven, Connecticut, 06510, United States

Location

Octapharma Research Site

Miami, Florida, 33136, United States

Location

Octapharma Research Site

Tampa, Florida, 33606, United States

Location

Octapharma Research Site

Iowa City, Iowa, 52242, United States

Location

Octapharma Research Site

Boston, Massachusetts, 02114, United States

Location

Octapharma Research Site

Rochester, New York, 14642, United States

Location

Octapharma Research Site

Durham, North Carolina, 27710, United States

Location

Octapharma Research Site

Cleveland, Ohio, 44109, United States

Location

Octapharma Research Site

Columbus, Ohio, 43210, United States

Location

Octapharma Research Site

Dayton, Ohio, 45409, United States

Location

Octapharma Research Site

Fairborn, Ohio, 45324, United States

Location

Octapharma Research Site

Pittsburgh, Pennsylvania, 15213, United States

Location

Octapharma Study Site

Pittsburgh, Pennsylvania, 15213, United States

Location

Octapharma Research Site

Pittsburgh, Pennsylvania, 15219, United States

Location

Octapharma Research Site

Pittsburgh, Pennsylvania, 15232, United States

Location

Octapharma Research Site

Pittsburgh, Pennsylvania, 15237, United States

Location

Octapharma Research Site (0115)

Austin, Texas, 78701, United States

Location

Octapharma Research Site (0127)

Austin, Texas, 78701, United States

Location

Octapharma Research Site

Dallas, Texas, 75390, United States

Location

Octapharma Research Site

Round Rock, Texas, 78665, United States

Location

Octapharma Research Site

Puyallup, Washington, 98374, United States

Location

Octapharma Research Site

Lesnoy, 223040, Belarus

Location

Octapharma Research Site

Minsk, 220024, Belarus

Location

Octapharma Research Site

Minsk, 220032, Belarus

Location

Octapharma Research Site

Minsk, 220040, Belarus

Location

Octapharma Research Site

Plovdiv, 4002, Bulgaria

Location

Octapharma Research Site

Rousse, 7002, Bulgaria

Location

Octapharma Research Site

Sofia, 1000, Bulgaria

Location

Octapharma Study Site

Sofia, 1000, Bulgaria

Location

Octapharma Research Site

Varna, 9010, Bulgaria

Location

Octapharma Research Site

Batumi, 6010, Georgia

Location

Octapharma Research Site

Kutaisi, 4600, Georgia

Location

Octapharma Research Site - Tbilisi

Tbilisi, 00114, Georgia

Location

Octapharma Research Location - Tbilisi

Tbilisi, 00167, Georgia

Location

Octapharma Research Site

Tbilisi, 0141, Georgia

Location

Octapharma Research Location

Tbilisi, 0159, Georgia

Location

Octapharma Research Site

Tbilisi, 0159, Georgia

Location

Octapharma Research Site

Zugdidi, 2100, Georgia

Location

Octapharma Research Site

Berlin, 12559, Germany

Location

Octapharma Research Site

Dresden, 01307, Germany

Location

Octapharma Research Site

Frankfurt am Main, 60590, Germany

Location

Octapharma Research Site

Heidelberg, 69120, Germany

Location

Octapharma Research Site

Chisinau, 2004, Moldova

Location

Octapharma Research Site

Bochnia, 32-700, Poland

Location

Octapharma Research Site

Lodz, 95-513, Poland

Location

Octapharma Research Site

Bucharest, 010825, Romania

Location

Octapharma Research Site

Bucharest, 020475, Romania

Location

Octapharma Research Site

Cluj-Napoca, 400006, Romania

Location

Octapharma Research Site

Craiova, 200624, Romania

Location

Octapharma Research Site

Oradea, 410167, Romania

Location

Octapharma Research Site

Timișoara, 3000723, Romania

Location

Octapharma Research Site

Moscow, Russian Federation, 105203, Russia

Location

Octapharma Research Site

Novosibirsk, Russian Federation, 630055, Russia

Location

Octapharma Research Site

Omsk, Russian Federation, 644111, Russia

Location

Octapharma Research Site

Saint Petersburg, Russian Federation, 192242, Russia

Location

Octapharma Research Site

Saint Petersburg, Russian Federation, 194354, Russia

Location

Octapharma Research Site

Saint Petersburg, Russian Federation, 197022, Russia

Location

Regional Clinical Hospital

Saratov, Russian Federation, 410053, Russia

Location

Octapharma Research Site

Tver', Russian Federation, 170036, Russia

Location

Octapharma Research Site

Yekaterinburg, Russian Federation, 620026, Russia

Location

Octapharma Research Site

Moscow, 111539, Russia

Location

Octapharma Research Site

Moscow, 115446, Russia

Location

Octapharma Research Site

Moscow, 124489, Russia

Location

Octapharma Research Site

Saint Petersburg, 194354, Russia

Location

Octapharma Research Site

Smolensk, 214019, Russia

Location

Octapharma Research Site

Barcelona, 08907, Spain

Location

Octapharma Research Site

Palma de Mallorca, 07120, Spain

Location

Octapharma Research Site

Valencia, 46026, Spain

Location

Octapharma Research Site

Cherkasy, 18009, Ukraine

Location

Octapharma Research Site

Chernivtsi, 58001, Ukraine

Location

Octapharma Research Location

Dnipro, 49005, Ukraine

Location

Octapharma Research Site

Dnipro, 49005, Ukraine

Location

Octapharma Research Site

Dnipro, 49102, Ukraine

Location

Octapharma Research Site

Ivano-Frankivsk, 76018, Ukraine

Location

Octapharma Research Site

Kharkiv, 61037, Ukraine

Location

Octapharma Research Site

Kharkiv, 61103, Ukraine

Location

Octapharma Research Site

Kropyvnytskyi, 25006, Ukraine

Location

Octapharma Research Site

Kyiv, 01133, Ukraine

Location

Octapharma Research Site

Lutsk, 43006, Ukraine

Location

Octapharma Research Site

Lviv, 79010, Ukraine

Location

Octapharma Research Site

Lviv, 79034, Ukraine

Location

Octapharma Research Site

Odesa, 65006, Ukraine

Location

Octapharma Research Site

Vinnytsia, 21018, Ukraine

Location

Octapharma Research Site

Zaporizhzhya, 69000, Ukraine

Location

Octapharma Research Site

Zhytomyr, 12430, Ukraine

Location

Related Publications (15)

• 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.

  PMID: 16810012 BACKGROUND

• Campbell P, Roberts G, Eaton V. Managing warfarin therapy in the community. Aust Prescriber 2001; 24:86-89.

  BACKGROUND

• 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.

  BACKGROUND

• Gohlke-Barwolf C. [Anticoagulation in surgery, after hemorrhagic complications and in pregnancy]. Z Kardiol. 1998;87 Suppl 4:56-62. German.

  PMID: 9857468 BACKGROUND

• 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.

  PMID: 25728933 BACKGROUND

• 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.

  PMID: 2281231 BACKGROUND

• 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.

  PMID: 21671894 BACKGROUND

• 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.

  PMID: 16689743 BACKGROUND

• 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.

  PMID: 9065997 BACKGROUND

• 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.

  PMID: 12424167 BACKGROUND

• 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.

  PMID: 8709780 BACKGROUND

• 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.

  PMID: 9403477 BACKGROUND

• 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.

  PMID: 16182346 BACKGROUND

• 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.

  PMID: 12586128 BACKGROUND

• Sarode R, Goldstein JN, Simonian G, Hinterberger D, Matveev D, Gareis M, Milling TJ Jr. Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates: A Randomized Clinical Trial. JAMA Netw Open. 2024 Aug 1;7(8):e2424758. doi: 10.1001/jamanetworkopen.2024.24758.

  PMID: 39088218 DERIVED

MeSH Terms

Conditions

Hemophilia B

Interventions

prothrombin complex concentrates; Factor IX; factor IX, factor VII, factor X, prothrombin drug combination

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked

Intervention Hierarchy (Ancestors)

Enzyme Precursors; Enzymes and Coenzymes; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Patrick Murphy
• Organization: Clinical Research Management Group

p.murphy@crmg-usa.com

413-821-0022

Study Officials

• Wolfgang Frenzel

  International Medical Monitor

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2016
• First Posted: April 15, 2016
• Study Start: June 8, 2017
• Primary Completion: February 23, 2022
• Study Completion: February 23, 2022
• Last Updated: March 8, 2023
• Results First Posted: March 8, 2023

Record last verified: 2023-03

Locations

DE (4); US (22); BE (4); MO (1); RU (14); GE (8); PL (2); ES (3); RO (6); BU (5); UA (17)