Phase 3 Evaluation of TAK-330 for Reversal of Direct Oral Factor Xa Inhibitor Anticoagulation in Patients Requiring Urgent Surgical Intervention
- Trial ID
- 2022-503012-16-00
- Protocol
- TAK-330-3001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **intraoperative efficacy** of TAK-330 compared to the standard of care (SOC) 4F-PCC for the reversal of anticoagulation in patients receiving direct oral Factor Xa inhibitors. This is clinically relevant as it addresses the urgent need for effective anticoagulation reversal in patients requiring urgent surgery or invasive procedures, particularly within 15 hours of the last dose of a Factor Xa inhibitor or when specific anti-FXa levels are elevated.
Secondary objectives include assessing the safety and postoperative efficacy of TAK-330 in comparison with SOC 4F-PCC. This evaluation is crucial for understanding the overall risk-benefit profile of TAK-330 in the context of urgent surgical interventions, ensuring that patients receive the most effective and safe treatment for anticoagulation reversal.
Participants
The clinical trial involves a total of **212 participants** who are currently undergoing treatment with oral **Factor Xa inhibitors** such as rivaroxaban, apixaban, or edoxaban. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to undergo urgent surgery or an invasive procedure associated with a high risk of bleeding within 15 hours of their last dose of a Factor Xa inhibitor, or at any time thereafter if elevated plasma anti-FXa levels are confirmed. The trial population was selected based on their current treatment regimen and the necessity for a reversal agent due to suspected direct oral Factor Xa inhibitor-related coagulopathy. The study includes individuals from a vulnerable population, and women of childbearing potential are required to have a negative pregnancy test prior to enrollment. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are those who require immediate medical intervention due to their anticoagulation status.
Plans and Procedures
The clinical trial is a **Phase 3**, prospective, randomized, open-label, adaptive group sequential, multicenter study with blinded endpoint assessment. The primary objective is 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 or invasive procedures. The trial is designed to compare TAK-330 with the standard of care (SOC) 4F-PCC. The study is expected to run from March 15, 2023, to May 12, 2028, with participant involvement lasting up to 30 days post-surgery or procedure.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, current treatment with oral Factor Xa inhibitors, and the necessity for urgent surgery due to high-risk bleeding. Women of childbearing potential must have a negative pregnancy test before enrollment. The trial includes follow-up visits to monitor intraoperative and postoperative hemostasis, adverse events, and any thrombotic events. The end-of-study visit will occur 30 days after the surgery or procedure to assess long-term outcomes.
Participants may be terminated early from the study if they experience serious adverse events, fail to comply with study procedures, or withdraw consent. The primary endpoint is the occurrence of intraoperative effective hemostasis, assessed using the Four Point Intraoperative Hemostatic Efficacy Scale. Secondary endpoints include postoperative hemostasis, usage of blood products, and the occurrence of adverse events within 30 days post-procedure. The trial aims to provide comprehensive data on the efficacy and safety of TAK-330 in this high-risk patient population.
Treatment
The clinical trial involves the administration of two treatments, one of which is the experimental medication **COAGULATION FACTOR IX, II, VII AND X IN COMBINATION**. This product is formulated as **PHF00230MIG** and is administered via **intravenous use**. The active substances in this formulation include **human coagulation factor IX**, **human coagulation factor VII**, and **protein S**. The dosage is measured in **IU/kg international unit(s)/kilogram**, with a maximum daily dose of 50 IU/kg and a total maximum dose of 50 IU/kg over a treatment period of one day. The pharmaceutical form is not specified beyond its code, and the product is not a pediatric formulation.
The comparator treatment in the study is **PROTHROMPLEX TOTAL®**, which is also administered via **intravenous use**. This product is a **solution for injection** and contains active substances such as **human coagulation factor IX**, **protein C**, **human coagulation factor VII**, **human coagulation factor II**, and **human coagulation factor X**. The dosage for this treatment is similarly measured in **IU/kg international unit(s)/kilogram**, with a maximum daily dose of 50 IU/kg and a total maximum dose of 50 IU/kg over a treatment period of one day. This product is not a pediatric formulation and serves as the standard-of-care therapy in the trial.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the occurrence of intraoperative effective hemostasis, which will be evaluated at the end of the surgery or invasive procedure. This assessment will be conducted by the principal investigator (PI), the surgeon, or a qualified member of the surgical team using the Four Point Intraoperative Hemostatic Efficacy Scale.
Secondary endpoints include the occurrence of postoperative effective hemostasis, assessed 24 hours after the end of the investigational product infusion (TAK-330 or comparator 4F-PCC), using the Four Point Postoperative Hemostatic Efficacy Scale. Additional secondary endpoints involve the usage of blood products or non-study hemostatic agents for bleeding control within 24 hours post-infusion, the number of units of packed red blood cells administered, and the occurrence of serious adverse events (SAEs), adverse events (AEs), treatment emergent AEs (TEAEs), and adverse events of special interest (AESIs) within 30 days post-procedure. The occurrence of thrombotic events and all-cause deaths within 30 days after the surgery or invasive procedure will also be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient or legally authorized representative willing to sign e-consent/written informed consent form (ICF).
- Patients ≥ 18 years of age at enrollment.
- Patient currently on treatment with oral Factor Xa inhibitor (rivaroxaban, apixaban, edoxaban).
- In the opinion of the surgeon, the patient requires urgent surgery/procedure that is associated with high-risk of intraoperative bleeding within 15 hours of the last Factor Xa inhibitor dose and requires a reversal agent for suspected direct oral Factor Xa inhibitor-related coagulopathy. In patients who are beyond the 15-hour window, eligibility requires proof of elevated plasma anti FXa levels using either specific DOAC-calibrated (apixaban, rivaroxaban or edoxaban) anti-FXa levels of > 75ng/mL, or heparin-calibrated anti-FXa assay levels of > 0.5 IU/mL at screening.
- Women of childbearing potential should have a negative pregnancy test documented prior to enrollment.
Exclusion Criteria
- The patient 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), 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 PRBC or intracranial hemorrhage with the exception of subacute and chronic subdural hemorrhages with a Glasgow Coma Score (GCS) ≥ 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 disorders (e.g., platelet function disorders, hemophilia, Von Willebrand disease, coagulation factor deficiency).
- Platelet count < 50,000/μL.
- History of heparin-induced thrombocytopenia.
- Administration of procoagulant drugs (e.g., non-study PCCs, recombinant Factor VIIa) or blood products (transfusion of whole blood, fresh frozen plasma (FFP), cryoglobulins, plasma fractions, or platelets) within 7 days before enrollment (Note: administration of packed red blood cells (PRBCs) for hemoglobin correction, tranexamic acid or aminocaproic acid are not exclusion criteria).
- Planned use of procoagulant drugs (e.g., Vitamin K, non-study PCCs, recombinant Factor VIIa) or blood products (transfusion of whole blood, FFP, cryoglobulins, plasma fractions, or platelets) after enrollment but before the 24±4 hours hemostatic assessment (Key secondary endpoint). Planned administration of TXA or aminocaproic acid after randomization but before the start of IP infusion, should be noted during randomization to properly stratify these patients in the IRT. Planned administration of TXA or aminocaproic acid after start of IP infusion but before the 24±4 hours hemostatic assessment is prohibited. Administration of any of the above products before the 24±4 hours hemostatic assessment will impact the assessment of hemostasis. Administration of PRBCs for hemoglobin correction, is not an exclusion criterion.
- 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.
- Patients 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) ≥ 65mmHg and having blood lactate > 2 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 patient at undue risk of harm if the patient 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. Participation in an observational study is not an exclusion criterion.
- The use of PROTHROMPLEX TOTAL as SOC 4F-PCC.
- Women who are breastfeeding at the time of enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 15 Mar 2023 | 14 |
 Belgium | Recruiting | 15 Mar 2023 | 24 |
 Czechia | Recruiting | 15 Mar 2023 | 17 |
 France | Recruiting | 15 Mar 2023 | 33 |
 Germany | Recruiting | 15 Mar 2023 | 14 |
 Greece | Recruiting | 15 Mar 2023 | 40 |
 Hungary | Recruiting | 15 Mar 2023 | 18 |
 The Netherlands | Not Recruiting | 15 Mar 2023 | — |
 Poland | Recruiting | 15 Mar 2023 | 20 |
 Portugal | Recruiting | 15 Mar 2023 | 13 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PROTHROMPLEX TOTAL® | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 50 | 1 | PRD10357149 |
COAGULATION FACTOR IX, II, VII AND X IN COMBINATION | Comparator | PHF00230MIG | INTRAVENOUS USE | 50 | 1 | SCP13269301 |