A Study of TAK-330 for Reversal of Direct Oral Factor Xa Inhibitor-induced Anticoagulation

Study Overview
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Brief Summary
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The aim of this study is to find out the effects of TAK-330 compared with four-factor prothrombin complex concentrate (4F-PCC) as part of standard treatment other than Prothromplex Total for anticoagulation reversal in participants treated with Factor Xa inhibitors who require urgent surgery/invasive procedure. The participant will be assigned by chance to either TAK-330 or SOC 4F-PCC as part of standard treatment before surgery. Patients participating in this study will need to be hospitalized. They will also be contacted (via telehealth/phone call) 30 days after the surgery.

Official Title
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A Phase 3, Prospective, Randomized, Open-label, Adaptive Group Sequential, Multicenter Trial With Blinded Endpoint Assessment to Evaluate the Efficacy and Safety of TAK-330 for the Reversal of Direct Oral Factor Xa Inhibitor-induced Anticoagulation in Patients Requiring Urgent Surgery/Invasive Procedure

Conditions
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Coagulation Disorder

Intervention / Treatment
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* Drug: TAK-330
* Drug: SOC 4F-PCC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant or legally authorized representative willing to sign e-consent/written informed consent form. Participants at least 18 years of age at enrollment. Participant currently on treatment with oral Factor Xa inhibitor (rivaroxaban, apixaban, edoxaban). In the opinion of the surgeon, the participant requires an urgent surgery/procedure that is associated with high-risk of intraoperative bleeding within 15 hours from the last dose of Factor Xa inhibitor and requires a reversal agent for suspected direct oral Factor Xa inhibitor-related coagulopathy. For participants who are beyond the 15-hour window, eligibility requires proof of elevated plasma anti Factor Xa (FXa) levels using either specific direct oral anti-coagulant (DOAC)-calibrated (apixaban, rivaroxaban or edoxaban) anti-FXa levels of greater than (>) 75 nanograms per milliliter (ng/mL), or heparin calibrated anti-FXa assay levels of >0.5 international unit per milliliter (IU/mL) at screening. Women of childbearing potential should have a negative pregnancy test documented prior to enrollment. Exclusion Criteria: The participant has an expected survival of less than 30 days, even with best available medical and surgical care. Recent history (within 90 days prior to screening) of venous thromboembolism, myocardial infarction (MI), disseminated intravascular coagulation (DIC), ischemic stroke, transient ischemic attack, hospitalization for unstable angina pectoris or severe or critical coronavirus 2 (SARS-CoV-2) infection. Active major bleeding defined as bleeding that requires surgery or transfusion of >2 units of packed red blood cell (PRBC) or intracranial hemorrhage with the exception of subacute and chronic subdural hemorrhages with a Glasgow Coma Score (GCS) greater than or equal to (>=) 9. Polytrauma for which reversal of Factor Xa-inhibition alone would not be sufficient to achieve hemostasis. Known prothrombotic disorder including primary antiphospholipid syndrome, antithrombin-3 deficiency, homozygous protein C deficiency, homozygous protein S deficiency, and homozygous factor V Leiden. Known bleeding disorder (eg, platelet function disorders, hemophilia, Von Willebrand disease, or coagulation factor deficiency). Platelet count less than (<) 50,000 per microliter (/mcL). History of heparin-induced thrombocytopenia. Administration of procoagulant drugs (eg, non-study prothrombin complex concentrates (PCCs), recombinant Factor VIIa) or blood products (transfusion of whole blood, fresh frozen plasma, cryoglobulins, plasma fractions, or platelets) within 7 days before enrollment. (Note: administration of PRBCs for hemoglobin correction, tranexamic acid or aminocaproic acid are not exclusion criteria). Planned use of procoagulant drugs (eg, Vitamin K, non-study PCCs, recombinant Factor VIIa) or blood products (transfusion of whole blood, fresh frozen plasma, cryoglobulins, plasma fractions, or platelets) after enrollment but before the investigational product infusion is initiated (Note: administration of PRBCs for hemoglobin correction, tranexamic acid or aminocaproic acid are not exclusion criteria). Administration of unfractionated heparin within 2 hours before randomization or low molecular weight heparin within 6 hours before randomization. Hypersensitivity to PCC constituents or any excipient of TAK-330. Participants with history of confirmed immunoglobulin A (IgA) deficiency with hypersensitivity reaction and antibodies to IgA. Septic shock as defined by persistent hypotension requiring vasopressors to maintain mean arterial pressure (MAP) >=65 millimeters of mercury (mmHg) and having blood lactate >2 millimole (mmol) despite adequate volume resuscitation. Acute or chronic liver failure (hepatic cirrhosis Child-PUGH score C) Renal failure requiring dialysis Any other condition that could, in the opinion of the investigator, put the participant at undue risk of harm if the participant were to participate in the study. Participation in another clinical study involving an investigational product or device within 30 days prior to study enrollment, or planned participation in another clinical study involving an investigational product or device during the course of this study. The use of PROTHROMPLEX TOTAL as SOC 4F-PCC. Women who are breastfeeding at the time of enrollment .

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Adaptive parallel-group sequential design.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-330 25 IU/kg<br>Participants will receive TAK-330, 25 international unit per kilogram (IU/kg) single intravenous infusion on Day 1 (prior to surgery) as an initial dose and an additional dose of 25 IU/kg TAK-330 can be administered during the surgery if deemed necessary by the surgeon. The total dose of TAK-330 administered to the participant should not exceed 50 IU/kg or 5,000 IU, whichever is smaller. | Drug: TAK-330<br>* Participants will receive TAK-330, 25 IU/kg single intravenous infusion on Day 1 and an additional dose of 25 IU/kg TAK-330 can be administered if required.<br>|
| Active Comparator: SOC 4F-PCC<br>Participants will receive 4F-PCC (excluding Prothromplex Total and activated 4F-PCC) as standard of care (SOC) on Day 1 (prior to surgery). The dose and infusion speed of the SOC 4F-PCC will be based on local institutional protocols. An additional dose of SOC 4F-PCC not exceeding total dose of 50 IU/kg or 5,000 IU, whichever is smaller can be given during the surgery if required. | Drug: SOC 4F-PCC<br>* Participants will receive 4F-PCC as SOC on Day 1. The dose and infusion speed of the SOC 4F-PCC will be based on local institutional protocols. An additional dose of SOC 4F-PCC not exceeding total dose of 50 IU/kg or 5,000 IU, whichever is smaller can be given during the surgery if required.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Intraoperative Effective Hemostasis | Percentage of participants with intraoperative effective hemostasis using Intraoperative Four Point Hemostatic Efficacy Scale that incorporates the surgeon's subjective opinion as to whether intraoperative hemostasis is sufficient and if there is the need for administration of non-study hemostatic treatments will be reported. | At the end of the surgery/procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Postoperative Effective Hemostasis | Percentage of participants with postoperative effective hemostasis using Postoperative Four Point Hemostatic Efficacy Scale based on the surgeon's assessment at 24 hours after the end of investigational product infusion will be reported. | At 24 hours after the end of investigational product infusion | 
| Percentage of Participants With Intraoperative Effective Hemostasis Based on Hemostatic Efficacy Rating Algorithm | Percentage of participants with intraoperative effective hemostasis based on hemostatic efficacy rating algorithm will be reported. The hemostatic efficacy rating (composite) algorithm incorporates the difference between predicted and actual bleeding during surgery, the surgeon's subjective opinion as to whether intraoperative hemostasis is sufficient, and the need for administration of non-study hemostatic treatments. | At the end of the surgery/procedure | 
| Number of Participants With Usage of Blood Products or Non-Study Hemostatic Agents for Bleeding Control | Number of participants with usage of blood products or non-study hemostatic agents for bleeding control will be documented from the end of IP infusion to 24 hours after end of study product infusion. | Within 24 hours after the end of investigational product infusion | 
| Number of Units of Packed Red Blood Cells (PRBCs) Administered to Achieve Bleeding Control | Number of units of PRBCs administered to achieve bleeding control within 24 hours after the end of IP infusion. | Within 24 hours after the end of investigational product infusion | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interests (AESIs) | An Adverse Event (AE) is defined as any untoward medical occurrence (including a symptom or disease or an abnormal laboratory finding) in a participant or clinical investigation participants administered a medicinal product and which does not necessarily have a causal relationship with the treatment. TEAEs are defined as those with a start date on or after the first dose of study treatment, or with a start date before the date of first dose of study treatment but increasing in severity after the first dose of study treatment. A SAE is any event that results in: death; life-threatening event; requires inpatient hospitalization or results in prolongation of existing hospitalization; persistent or significant disability/incapacity; results in a congenital anomaly/birth defect or a medically important event. AESI will include hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. | Within 30 days after the end of the surgery/invasive procedure (up to 33 days) | 
| Number of Participants With Thrombotic Events | Number of thrombotic events within 30 days after the end of the surgery/invasive procedure will be assessed. Thrombotic events occur when a blood clot, known as a thrombus, is formed within a blood vessel. It prevents blood from flowing normally through the circulatory system. | Within 30 days after the end of the surgery/invasive procedure (up to 33 days) | 
| Number of Participants With Deaths Within 30 Days Post-Surgery/Invasive Procedure | Number of deaths Within 30 days post-surgery/invasive procedure will be assessed. | Within 30 days post-surgery/invasive procedure (up to 33 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reversal of Factor Xa inhibitors