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    Summary
    EudraCT Number:2021-004138-12
    Sponsor's Protocol Code Number:TAK-330-3001
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-04-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2021-004138-12
    A.3Full title of the trial
    A Phase 3, Prospective, Randomized, Open-label, Adaptive Group Sequential, Multicenter Trial with Blinded Endpoint Assessment to Evaluate the Efficacy and Safety of PROTHROMPLEX TOTAL for the Reversal of Direct Oral Factor Xa Inhibitor-induced Anticoagulation in Patients Requiring Urgent Surgery/Invasive Procedure
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Trial of PROTHROMPLEX TOTAL for Reversal of Direct Oral Factor Xa Inhibitor-induced Anticoagulation
    A.4.1Sponsor's protocol code numberTAK-330-3001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Development Center Americas, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTakeda Development Center Americas, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc.
    B.5.2Functional name of contact pointHead of Global Clinical Operations
    B.5.3 Address:
    B.5.3.1Street Address300 Massachusetts Avenue
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617444 2435
    B.5.6E-mailkaren.correa@takeda.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Prothromplex TOTAL 600 IU powder and solvent for solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holder[To be completed nationally]
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameProthromplex TOTAL
    D.3.2Product code TAK-330
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Coagulation Factors II, VII, IX, and X
    D.3.9.2Current sponsor codeTAK-330
    D.3.9.3Other descriptive nameHUMAN PROTHROMBIN COMPLEX
    D.3.9.4EV Substance CodeSUB12044MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Any 4-factor PCC that is used by the institution as a part of local SOC treatment to achieve hemostasis
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Coagulation Factors II, VII, IX, and X
    D.3.9.3Other descriptive nameHUMAN PROTHROMBIN COMPLEX
    D.3.9.4EV Substance CodeSUB12044MIG
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients on treatment with Factor Xa Inhibitor needing for an urgent intervention associated with a high risk of bleeding.
    E.1.1.1Medical condition in easily understood language
    Patients on treatment with certain blood thinners called Factor 10a inhibitors are at increased risk of developing serious bleeding during urgent surgery.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075279
    E.1.2Term Anticoagulant reversal therapy
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate intraoperative efficacy of PROTHROMPLEX TOTAL in comparison with standard of care (SOC) 4-factor prothrombin complex concentrate (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.
    E.2.2Secondary objectives of the trial
    To assess the safety and postoperative efficacy of PROTHROMPLEX TOTAL 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.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject or legally authorized representative willing to sign e-consent/written informed consent form.
    2. Subjects ≥18 years of age at enrollment.
    3. Subject currently on treatment with oral Factor Xa inhibitor (rivaroxaban, apixaban, edoxaban).
    4. In the opinion of the surgeon, the subject requires urgent surgery/procedure within 15 hours of the last Factor Xa inhibitor dose and requires a reversal agent for suspected direct oral Factor Xa inhibitor-related coagulopathy.
    5. Women of childbearing potential should have a negative pregnancy test documented prior to enrollment.
    E.4Principal exclusion criteria
    1. The subject has an expected survival of less than 30 days, even with best available medical and surgical care.
    2. Recent history (within 90 days before screening) of venous thromboembolism, myocardial infarction, disseminated intravascular coagulation, ischemic stroke, transient ischemic attack, hospitalization for unstable angina pectoris, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, or severe peripheral vascular disease.
    3. Acute major bleeding, defined as bleeding that requires surgery or transfusion of ≥2 units of packed red blood cells (PRBCs) or is associated with a decrease in hemoglobin of ≥1.0 g/dL, or intracranial hemorrhage.
    4. Acute trauma 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 disorder (eg, platelet function disorder, hemophilia, Von Willebrand disease, or coagulation factor deficiency).
    7. Platelet count <100,000/μL.
    8. History of heparin-induced thrombocytopenia.
    9. Administration of procoagulant drugs (eg, Vitamin K, non-study prothrombin complex concentrates (PCCs), recombinant Factor VIIa, tranexamic acid) 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 is not an exclusion criterion).
    10. Planned use of procoagulant drugs (eg, Vitamin K, non-study PCCs, recombinant Factor VIIa, tranexamic acid) 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 is not an exclusion criterion).
    11. Administration of unfractionated or low molecular weight heparin within 24 hours before randomization.
    12. Hypersensitivity to PCC constituents or any excipient of PROTHROMPLEX TOTAL.
    13. Confirmed or suspected sepsis.
    E.5 End points
    E.5.1Primary end point(s)
    Occurrence of intraoperative effective hemostasis based on the surgeon's assessment at the end of the
    surgery/invasive procedure using the Four Point Intraoperative Hemostatic Efficacy Scale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of the surgery
    E.5.2Secondary end point(s)
    Key Secondary Endpoint: Occurrence of postoperative effective hemostasis based on the surgeon's assessment at 24 hours after the end of investigational product infusion (PROTHROMPLEX TOTAL or comparator 4F-PCC) using the Four Point Postoperative Hemostatic Efficacy Scale.

    1. Occurrence of intraoperative effective hemostasis based on the surgeon’s assessment using the Hemostatic Efficacy Rating Algorithm.
    2. Usage of blood products or non-study hemostatic agents for bleeding control within 24 hours after the end of investigational product infusion.
    3. Number of units of packed red blood cells administered to achieve bleeding control within 24 hours after the end of investigational product infusion.
    4. 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.
    5. Occurrence of thrombotic events within 30 days after the end of the surgery/invasive procedure.
    6. All-cause deaths within 30 days post-surgery/invasive procedure.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key Secondary Endpoint: 24 hours after the end of investigational product infusion
    1. End of the surgery
    2. & 3. Within 24 hours after the end of investigational product infusion.
    4.- 6. Within 30 days post-surgery/invasive procedure.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    The surgeon and the Independent Endpoint Adjudication Committee will be blinded to the treatment.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    China
    India
    Japan
    Korea, Republic of
    Russian Federation
    Taiwan
    Thailand
    United States
    Viet Nam
    Austria
    Belgium
    Finland
    France
    Germany
    Italy
    Sweden
    Bulgaria
    Netherlands
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study completion date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months18
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 550
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-06-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-26
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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