Clinical trial NCT02740335: 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.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Significant Bleeding Risk
Keywords: anticoagulant reversal
urgent surgery
invasive procedures
vitamin K
prothrombin complex concentrate
four-factor prothrombin complex concentrate (4F-PCC)
Lead sponsor: Octapharma
Sponsor class: INDUSTRY
First posted: 2016-04-15
Enrollment: 208
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Hemostatic Efficacy Rating by IEAB
timeFrame: At the end of the surgery
measure: Dichotomous Hemostasis Success
timeFrame: At the end of surgery
Secondary outcomes:
measure: Measuring of International Normalized Ratio (INR) to ≤ 1.5
timeFrame: 30 minutes after the end of infusion
measure: Coagulation Factor II Levels
timeFrame: 30 minutes after the end of infusion
measure: Coagulation Factor VII Levels
timeFrame: 30 minutes after the end of infusion
measure: Coagulation Factor IX Levels
timeFrame: 30 minutes after the end of infusion
measure: Coagulation Factor X Levels
timeFrame: 30 minutes after the end of infusion
measure: Number of Patients Requiring Red Blood Cells (RBC)
timeFrame: At the end of surgery
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Octapharma Research Site
state: Colorado
city: New Haven
country: United States
facility: Octapharma Research Site
state: Connecticut
city: Miami
country: United States
facility: Octapharma Research Site
state: Florida
city: Tampa
country: United States
facility: Octapharma Research Site
state: Florida
city: Iowa City
country: United States
facility: Octapharma Research Site
state: Iowa
city: Boston
country: United States
facility: Octapharma Research Site
state: Massachusetts
city: Rochester
country: United States
facility: Octapharma Research Site
state: New York
city: Durham
country: United States
facility: Octapharma Research Site
state: North Carolina
city: Cleveland
country: United States
facility: Octapharma Research Site
state: Ohio
city: Columbus
country: United States
facility: Octapharma Research Site
state: Ohio
city: Dayton
country: United States
facility: Octapharma Research Site
state: Ohio
city: Fairborn
country: United States
facility: Octapharma Research Site
state: Ohio
city: Pittsburgh
country: United States
facility: Octapharma Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Octapharma Study Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Octapharma Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Octapharma Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Octapharma Research Site
state: Pennsylvania
city: Austin
country: United States
facility: Octapharma Research Site (0115)
state: Texas
city: Austin
country: United States
facility: Octapharma Research Site (0127)
state: Texas
city: Dallas
country: United States
facility: Octapharma Research Site
state: Texas
city: Round Rock
country: United States
facility: Octapharma Research Site
state: Texas
city: Puyallup
country: United States
facility: Octapharma Research Site
state: Washington
city: Lesnoy
country: Belarus
facility: Octapharma Research Site
city: Minsk
country: Belarus
facility: Octapharma Research Site
city: Minsk
country: Belarus
facility: Octapharma Research Site
city: Minsk
country: Belarus
facility: Octapharma Research Site
city: Plovdiv
country: Bulgaria
facility: Octapharma Research Site
city: Ruse
country: Bulgaria
facility: Octapharma Research Site
city: Sofia
country: Bulgaria
facility: Octapharma Research Site
city: Sofia
country: Bulgaria
facility: Octapharma Study Site
city: Varna
country: Bulgaria
facility: Octapharma Research Site
city: Batumi
country: Georgia
facility: Octapharma Research Site
city: Kutaisi
country: Georgia
facility: Octapharma Research Site
city: Tbilisi
country: Georgia
facility: Octapharma Research Site - Tbilisi
city: Tbilisi
country: Georgia
facility: Octapharma Research Location - Tbilisi
city: Tbilisi
country: Georgia
facility: Octapharma Research Site
city: Tbilisi
country: Georgia
facility: Octapharma Research Location
city: Tbilisi
country: Georgia
facility: Octapharma Research Site
city: Zugdidi
country: Georgia
facility: Octapharma Research Site
city: Berlin
country: Germany
facility: Octapharma Research Site
city: Dresden
country: Germany
facility: Octapharma Research Site
city: Frankfurt am Main
country: Germany
facility: Octapharma Research Site
city: Heidelberg
country: Germany
facility: Octapharma Research Site
city: Chisinau
country: Moldova, Republic of
facility: Octapharma Research Site
city: Bochnia
country: Poland
facility: Octapharma Research Site
city: Łódź
country: Poland
facility: Octapharma Research Site
city: Bucharest
country: Romania
facility: Octapharma Research Site
city: Bucharest
country: Romania
facility: Octapharma Research Site
city: Cluj-Napoca
country: Romania
facility: Octapharma Research Site
city: Craiova
country: Romania
facility: Octapharma Research Site
city: Oradea
country: Romania
facility: Octapharma Research Site
city: Timişoara
country: Romania
facility: Octapharma Research Site
city: Moscow
country: Russian Federation
facility: Octapharma Research Site
city: Moscow
country: Russian Federation
facility: Octapharma Research Site
city: Moscow
country: Russian Federation
facility: Octapharma Research Site
city: Moscow
country: Russian Federation
facility: Octapharma Research Site
city: Novosibirsk
country: Russian Federation
facility: Octapharma Research Site
city: Omsk
country: Russian Federation
facility: Octapharma Research Site
city: Saint Petersburg
country: Russian Federation
facility: Octapharma Research Site
city: Saint Petersburg
country: Russian Federation
facility: Octapharma Research Site
city: Saint Petersburg
country: Russian Federation
facility: Octapharma Research Site
city: Saratov
country: Russian Federation
facility: Regional Clinical Hospital
city: Smolensk
country: Russian Federation
facility: Octapharma Research Site
city: Tver
country: Russian Federation
facility: Octapharma Research Site
city: Yekaterinburg
country: Russian Federation
facility: Octapharma Research Site
city: Barcelona
country: Spain
facility: Octapharma Research Site
city: Palma De Mallorca
country: Spain
facility: Octapharma Research Site
city: Valencia
country: Spain
facility: Octapharma Research Site
city: Cherkasy
country: Ukraine
facility: Octapharma Research Site
city: Chernivtsi
country: Ukraine
facility: Octapharma Research Site
city: Dnipro
country: Ukraine
facility: Octapharma Research Location
city: Dnipro
country: Ukraine
facility: Octapharma Research Site
city: Dnipro
country: Ukraine
facility: Octapharma Research Site
city: Ivano-Frankivs'k
country: Ukraine
facility: Octapharma Research Site
city: Kharkiv
country: Ukraine
facility: Octapharma Research Site
city: Kharkiv
country: Ukraine
facility: Octapharma Research Site
city: Kropyvnytskyi
country: Ukraine
facility: Octapharma Research Site
city: Kyiv
country: Ukraine
facility: Octapharma Research Site
city: L'viv
country: Ukraine
facility: Octapharma Research Site
city: Luts'k
country: Ukraine
facility: Octapharma Research Site
city: Lviv
country: Ukraine
facility: Octapharma Research Site
city: Odesa
country: Ukraine
facility: Octapharma Research Site
city: Vinnytsia
country: Ukraine
facility: Octapharma Research Site
city: Vinnytsya
country: Ukraine
facility: Octapharma Research Site
city: Zaporizhzhya
country: Ukraine
facility: Octapharma Research Site
city: Zhytomyr
country: Ukraine
facility: Octapharma Research Site
Study officials:
affiliation: International Medical Monitor
name: Wolfgang Frenzel
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Campbell P, Roberts G, Eaton V. Managing warfarin therapy in the community. Aust Prescriber 2001; 24:86-89.
citation: 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.
citation: Gohlke-Barwolf C. [Anticoagulation in surgery, after hemorrhagic complications and in pregnancy]. Z Kardiol. 1998;87 Suppl 4:56-62. German.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.