Phase 3 Trial of TAK-330 for Reversal of Direct Oral Factor Xa Inhibitor-induced Anticoagulation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

20 Jul 2022 → ongoing

Decision date (initial)

2023-07-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2022-503012-16-00

EudraCT number

2021-004138-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate intraoperative efficacy of TAK-330 in comparison with standard of care (SOC) 4F-PCC, for reversal of anticoagulation in patients receiving direct oral Factor Xa inhibitors and requiring urgent surgery/invasive procedure within 15 hours from the last dose of Factor Xa inhibitor or at any time after that if their specific DOAC calibrated (apixaban, rivaroxaban or edoxaban) anti-FXa levels were > 75ng/mL or heparin-calibrated anti FXa assay level of > 0.5 IU/mL at screening.

Secondary objectives 1

1. To assess the safety and postoperative efficacy of TAK 330 in comparison with SOC 4F-PCC, for reversal of anticoagulation in patients receiving direct oral Factor Xa inhibitors and requiring urgent surgery/invasive procedure within 15 hours of the last dose of Factor Xa inhibitor, or at any time after that if their specific DOAC-calibrated (apixaban, rivaroxaban or edoxaban) anti-FXa levels were > 75ng/mL, or heparin-calibrated anti-FXa assay levels of > 0.5 IU/mL at screening.

Conditions and MedDRA coding

Patients on treatment with Factor Xa Inhibitor needing for an urgent intervention associated with a high risk of bleeding.

Regulatory references

Scientific advice from competent authorities

Austrian Federal Office For Safety In Health Care

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patient or legally authorized representative willing to sign e-consent/written informed consent form (ICF).
2. Patients ≥ 18 years of age at enrollment.
3. Patient currently on treatment with oral Factor Xa inhibitor (rivaroxaban, apixaban, edoxaban).
4. 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.
5. Women of childbearing potential should have a negative pregnancy test documented prior to enrollment.

Exclusion criteria 20

1. The patient has an expected survival of less than 30 days even with best available medical and surgical care.
2. 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.
3. 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.
4. Polytrauma for which reversal of Factor Xa-inhibition alone would not be sufficient to achieve hemostasis.
5. Known prothrombotic disorder including primary antiphospholipid syndrome, antithrombin-3 deficiency, homozygous protein C deficiency, homozygous protein S deficiency, and homozygous factor V Leiden.
6. Known bleeding disorders (e.g., platelet function disorders, hemophilia, Von Willebrand disease, coagulation factor deficiency).
7. Platelet count < 50,000/μL.
8. History of heparin-induced thrombocytopenia.
9. 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).
10. 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.
11. Administration of unfractionated heparin within 2 hours before randomization or low molecular weight heparin within 6 hours before randomization.
12. Hypersensitivity to PCC constituents, or any excipient of TAK-330.
13. Patients with history of confirmed immunoglobulin A (IgA) deficiency with hypersensitivity reaction and antibodies to IgA.
14. 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.
15. Acute or chronic liver failure (hepatic cirrhosis Child-PUGH score C).
16. Renal failure requiring dialysis.
17. 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.
18. 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.
19. The use of PROTHROMPLEX TOTAL as SOC 4F-PCC.
20. Women who are breastfeeding at the time of enrollment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Occurrence of intraoperative effective hemostasis assessed at the end of the surgery/invasive procedure based on the assessment of the PI, the surgeon or a qualified member of the surgical team using the Four Point Intraoperative Hemostatic Efficacy Scale (Section 8.2.2.1).

Secondary endpoints 7

1. Key Secondary Endpoint: Occurrence of postoperative effective hemostasis assessed at 24 hours after the end of investigational product infusion (TAK-330 or comparator 4F-PCC) based on the assessment of the PI, the surgeon or a qualified member of the surgical team using the Four Point Postoperative Hemostatic Efficacy Scale (Section 8.2.2.1).
2. • Occurrence of intraoperative effective hemostasis assessed at the end of the surgery/invasive procedure based on the assessment of the PI, the surgeon or a qualified member of the surgical team using the Hemostatic Efficacy Rating Algorithm (Section 8.2.2.2).
3. • Usage of blood products or non-study hemostatic agents for bleeding control within 24 hours after the end of investigational product infusion.
4. • Number of units of packed red blood cells (PRBCs) administered to achieve bleeding control within 24 hours after the end of investigational product infusion.
5. • Occurrence of serious adverse events (SAEs), and/or adverse events (AEs), treatment emergent AEs (TEAEs), and adverse events of special interest (AESIs) within 30 days after the end of the surgery/invasive procedure.
6. • Occurrence of thrombotic events within 30 days after the end of the surgery/invasive procedure.
7. • All-cause deaths within 30 days post-surgery/invasive procedure.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 8

Locations

11 EU/EEA countries · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 232 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

27 submissions — initial application plus substantial / non-substantial modifications