A Study of TAK-330 to Reverse the Effects of Factor Xa Inhibitors For Adults Needing Urgent Surgery

Official title

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

Overview

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.

Interventions

• Drug TAK-330
  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.
• Drug SOC 4F-PCC
  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.

Primary outcome measures

• Percentage of Participants With Intraoperative Effective Hemostasis [Time frame: At the end of the surgery/procedure]

Secondary outcome measures (7)

• Percentage of Participants With Postoperative Effective Hemostasis [Time frame: At 24 hours after the end of investigational product infusion]
• Percentage of Participants With Intraoperative Effective Hemostasis Based on Hemostatic Efficacy Rating Algorithm [Time frame: At the end of the surgery/procedure]
• Number of Participants With Usage of Blood Products or Non-Study Hemostatic Agents for Bleeding Control [Time frame: Within 24 hours after the end of investigational product infusion]
• Number of Units of Packed Red Blood Cells (PRBCs) Administered to Achieve Bleeding Control [Time frame: 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) [Time frame: Within 30 days after the end of the surgery/invasive procedure (up to 33 days)]
• Number of Participants With Thrombotic Events [Time frame: 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 [Time frame: Within 30 days post-surgery/invasive procedure (up to 33 days)]

Eligibility criteria

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 (example, 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 (example, 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 (example, 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 24±4 hours hemostatic assessment (Key secondary endpoint). Planned administration of tranexamic acid (TXA) or aminocaproic acid after randomization but before the start of IP infusion, should be noted during randomization to properly stratify these participants in the interactive response technology (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.
• 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. 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 13 centers

• University of Arkansas Medical Sciences — Arkansas City
• University of California Davis Health System — Sacramento
• Denver Metro Orthopedics, P.C. — Englewood
• University of Florida — Gainesville
• Rutgers, The State University of New Jersey — New Brunswick
• ECU Health Medical Center — Greenville
• Metro Health Medical Center — Cleveland
• Ohio State University — Columbus
• … and 5 more centers

Israel · 8 centers

• Shamir Medical Center (Assaf Harofe) — Beer Yaacov
• Soroka Medical Center — Beersheba
• Rambam Health Care Campus — Haifa
• Shaare Zedek Medical Center — Jerusalem
• Hadassah University Hospital - Ein Kerem — Jerusalem
• Rabin MC — Petah Tikva
• Chaim Sheba Medical Center — Ramat Gan
• Tel Aviv Sourasky Medical Center — Tel Aviv

Canada · 6 centers

• Hamilton General Hospital — Hamilton
• London Health Sciences Centre (LHSC) - University Hospital — London
• Unity Health Toronto St Michaels Hospital — Toronto
• Montreal General Hospital — Montreal
• The Ottawa Hospital - General Campus — Ontario
• CHU de Quebec- Hopital de l Enfant Jesus — Québec

France · 5 centers

• CHU Strasbourg - Hopital Hautepierre — Strasbourg
• Hospital michallon - CHUGA — Grenoble
• Hopital Marie Lannelongue — Le Plessis-Robinson
• Hôpital Lariboisière — Paris
• GH Paris Saint Joseph — Paris

Argentina · 4 centers

• Hospital Universitario Austral — Buenos Aires
• Clinica Zabala — Ciudad Autonoma Buenos Aires
• Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia - FLENI — Ciudad Autonoma Buenos Aires
• Hospital Privado de Rosario — Santa Fe

Belgium · 4 centers

• ZOL — Genk
• Jessa Ziekenhuis Hospital — Hasselt
• AZ Groeninge — Kortrijk
• CHU UCL Namur — Therasse 1

Germany · 4 centers

• BG Klinikum Murnau gGmbH — Murnau am Staffelsee
• Universitaetsklinikum Carl Gustav Carus TU Dresden — Dresden
• Universitaetsklinikum Leipzig AoeR — Leipzig
• Klinikum Dortmund gGmbH — Murnau am Staffelsee

Hungary · 4 centers

• Bekes Varmegyei Kozponti Korhaz — Békéscsaba
• Ozdi Almasi Balogh Pal Korhaz — Szeged
• Semmelweis Egyetem — Budapest
• Debreceni Egyetem — Debrecen

Brazil · 3 centers

• Irmandade da Santa Casa da Misericordia de Santos — Santos
• Hospital de Clinicas de Ijui — Ijuí
• Hospital Sao Paulo — São Paulo

Czechia · 3 centers

• Fakultni nemocnice Brno — Jihlavska
• Fakultni nemocnice v Motole — Prague (Praha)
• Dept of II. interni klinika - gastroenterologie — Srobarova C

Portugal · 3 centers

• Centro Hospitalar do Baixo Vouga, E.P.E. - Unidade de Aveiro — Aveiro
• Centro Hospitalar do Baixo Vouga, E.P.E. - Unidade de Aveiro — Aveiro
• Centro Hospitalar de Vila Nova de Gaia/Espinho, E.P.E — Rua Conceição Fernandes

Spain · 3 centers

• Hospital Clinico Universitario de Salamanca — Salamnca
• Hospital Clinico Universitario de Valencia — Valencia
• Hospital Universitari i Politecnic La Fe — Valencia

Austria · 2 centers

• LKH - Universitaetsklinikum Graz — Graz
• Landesklinikum Neunkirchen — Neunkirchen

Greece · 1 center

• Konstantopoulio General Hospital, N.Ionia — Nea Ionia

Poland · 1 center

• Uniwersytecki Szpital Kliniczny nr 1 im. prof. Tadeusza Sokołowskiego PUM w Szczecinie — Szczecin

Identifiers

NCT: NCT05156983 · TAK-330-3001 · 2021-004138-12 · 2022-503012-16-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗