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.

Significant Bleeding Risk Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02740335
• Other study ID #: LEX-209
• Status: Completed
• Phase: Phase 3
• Start date: June 8, 2017
• Est. completion date: February 23, 2022

Study information

• Verified date: March 2023
• Source: Octapharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 208
• Est. completion date: February 23, 2022
• Est. primary completion date: February 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemorrhage
• Significant Bleeding Risk

Intervention

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).
• 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).

Locations

Country	Name	City	State
Belarus	Octapharma Research Site	Lesnoy
Belarus	Octapharma Research Site	Minsk
Belarus	Octapharma Research Site	Minsk
Belarus	Octapharma Research Site	Minsk
Bulgaria	Octapharma Research Site	Plovdiv
Bulgaria	Octapharma Research Site	Ruse
Bulgaria	Octapharma Research Site	Sofia
Bulgaria	Octapharma Study Site	Sofia
Bulgaria	Octapharma Research Site	Varna
Georgia	Octapharma Research Site	Batumi
Georgia	Octapharma Research Site	Kutaisi
Georgia	Octapharma Research Location	Tbilisi
Georgia	Octapharma Research Location - Tbilisi	Tbilisi
Georgia	Octapharma Research Site	Tbilisi
Georgia	Octapharma Research Site	Tbilisi
Georgia	Octapharma Research Site - Tbilisi	Tbilisi
Georgia	Octapharma Research Site	Zugdidi
Germany	Octapharma Research Site	Berlin
Germany	Octapharma Research Site	Dresden
Germany	Octapharma Research Site	Frankfurt am Main
Germany	Octapharma Research Site	Heidelberg
Moldova, Republic of	Octapharma Research Site	Chisinau
Poland	Octapharma Research Site	Bochnia
Poland	Octapharma Research Site	Lódz
Romania	Octapharma Research Site	Bucharest
Romania	Octapharma Research Site	Bucharest
Romania	Octapharma Research Site	Cluj-Napoca
Romania	Octapharma Research Site	Craiova
Romania	Octapharma Research Site	Oradea
Romania	Octapharma Research Site	Timisoara
Russian Federation	Octapharma Research Site	Moscow
Russian Federation	Octapharma Research Site	Moscow
Russian Federation	Octapharma Research Site	Moscow
Russian Federation	Octapharma Research Site	Moscow
Russian Federation	Octapharma Research Site	Novosibirsk
Russian Federation	Octapharma Research Site	Omsk
Russian Federation	Octapharma Research Site	Saint Petersburg
Russian Federation	Octapharma Research Site	Saint Petersburg
Russian Federation	Octapharma Research Site	Saint Petersburg
Russian Federation	Regional Clinical Hospital	Saratov
Russian Federation	Octapharma Research Site	Smolensk
Russian Federation	Octapharma Research Site	Tver
Russian Federation	Octapharma Research Site	Yekaterinburg
Spain	Octapharma Research Site	Barcelona
Spain	Octapharma Research Site	Palma De Mallorca
Spain	Octapharma Research Site	Valencia
Ukraine	Octapharma Research Site	Cherkasy
Ukraine	Octapharma Research Site	Chernivtsi
Ukraine	Octapharma Research Location	Dnipro
Ukraine	Octapharma Research Site	Dnipro
Ukraine	Octapharma Research Site	Dnipro
Ukraine	Octapharma Research Site	Ivano-Frankivs'k
Ukraine	Octapharma Research Site	Kharkiv
Ukraine	Octapharma Research Site	Kharkiv
Ukraine	Octapharma Research Site	Kropyvnytskyi
Ukraine	Octapharma Research Site	Kyiv
Ukraine	Octapharma Research Site	L'viv
Ukraine	Octapharma Research Site	Luts'k
Ukraine	Octapharma Research Site	Lviv
Ukraine	Octapharma Research Site	Odesa
Ukraine	Octapharma Research Site	Vinnytsia
Ukraine	Octapharma Research Site	Vinnytsya
Ukraine	Octapharma Research Site	Zaporizhzhya
Ukraine	Octapharma Research Site	Zhytomyr
United States	Octapharma Research Site	Aurora	Colorado
United States	Octapharma Research Site (0115)	Austin	Texas
United States	Octapharma Research Site (0127)	Austin	Texas
United States	Octapharma Research Site	Boston	Massachusetts
United States	Octapharma Research Site	Cleveland	Ohio
United States	Octapharma Research Site	Columbus	Ohio
United States	Octapharma Research Site	Dallas	Texas
United States	Octapharma Research Site	Dayton	Ohio
United States	Octapharma Research Site	Durham	North Carolina
United States	Octapharma Research Site	Fairborn	Ohio
United States	Octapharma Research Site	Iowa City	Iowa
United States	Octapharma Research Site	Miami	Florida
United States	Octapharma Research Site	New Haven	Connecticut
United States	Octapharma Research Site	Pittsburgh	Pennsylvania
United States	Octapharma Research Site	Pittsburgh	Pennsylvania
United States	Octapharma Research Site	Pittsburgh	Pennsylvania
United States	Octapharma Research Site	Pittsburgh	Pennsylvania
United States	Octapharma Study Site	Pittsburgh	Pennsylvania
United States	Octapharma Research Site	Puyallup	Washington
United States	Octapharma Research Site	Rochester	New York
United States	Octapharma Research Site	Round Rock	Texas
United States	Octapharma Research Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Octapharma

Countries where clinical trial is conducted

United States,  Belarus,  Bulgaria,  Georgia,  Germany,  Moldova, Republic of,  Poland,  Romania,  Russian Federation,  Spain,  Ukraine, 

References & Publications (14)

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. — View 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. — View Citation

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	At the end of the surgery
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	At the end of surgery
Secondary	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
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.	30 minutes after the end of infusion
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of Patients Requiring Red Blood Cells (RBC)	Number of patients receiving red blood cells (RBC) during the surgery	At the end of surgery