E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients on treatment with Factor Xa Inhibitor needing for an urgent intervention associated with a high risk of bleeding. |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075279 |
E.1.2 | Term | Anticoagulant reversal therapy |
E.1.2 | System Organ Class | 100000004865 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The surgeon and the Independent Endpoint Adjudication Committee will be blinded to the treatment. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 18 |
E.8.9.2 | In all countries concerned by the trial days | 0 |