E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute major bleeding in patients receiving DOAC therapy with factor Xa inhibitor |
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E.1.1.1 | Medical condition in easily understood language |
Acute major bleeding in patients on oral anticoagulants |
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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 | 10009731 |
E.1.2 | Term | Coagulation disorder |
E.1.2 | System Organ Class | 100000004851 |
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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 demonstrate superior haemostatic effectiveness of OCTAPLEX dosed at 50 IU/Kg body weight vs. 15 IU/Kg body weight for emergency reversal of the anticoagulant effect of DOACs in patients with major bleeding associated with factor Xa inhibition. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of OCTAPLEX on thrombin generation in patients with acute major bleeding on DOAC therapy with factor Xa inhibitor.
To evaluate the safety of OCTAPLEX in patients with acute major bleeding on DOAC therapy with factor Xa inhibitor. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients who received or who are believed by the investigator to have received a dose of oral factor Xa inhibitor
• Aged ≥18 years
• Patients who have given written informed consent or for whom written informed consent has been obtained from the patient's legally authorised representative on their behalf
• Patients who have acute major bleeding defined as follows:
- Bleeding that is potentially life-threatening or uncontrolled, e.g., with signs or symptoms of haemodynamic compromise, such as severe hypotension, poor skin perfusion, or low cardiac output that cannot be otherwise explained
OR
- Symptomatic bleeding in critical organs (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome)
OR
- Acute overt bleeding associated with a fall in haemoglobin (Hgb) level of ≥2 g/dL, OR a Hgb level ≤8 g/dL if no baseline Hgb level is available, OR in the opinion of the investigator that the patient’s Hgb level will fall to ≤8 g/dL with resuscitation
• Patients with baseline anti-factor Xa activity equivalent to at least 100 ng/mL according to the available test (e.g., chromogenic assay) |
|
E.4 | Principal exclusion criteria |
• Patients with bleeding that is immediately life-threatening
• Patients with ‘Do not resuscitate’ (DNR) orders
• Patients with acute trauma for which reversal of DOAC therapy with factor Xa inhibitor alone would not be expected to control the bleeding event
• Hgb decrease without accompanying evidence of source of bleeding
• Acute coronary syndrome, ischaemic stroke or venous thromboembolism (VTE) within the preceding 3 months
• Patients with a history, within the last 3 months, of disseminated intravascular coagulation (DIC) or hyperfibrinolysis
• Patients with a known congenital coagulation disorder
• Known inhibitors to coagulation factors II, VII, IX, or X; or heparin-induced, type II thrombocytopenia
• Known hypersensitivity to plasma-derived products
• Patients who received haemostatic agents, including plasma, platelets, PCC, activated PCC (aPCC), recombinant factor VIIa, or recombinant factor Xa inactivated-zhzo (andexanet alfa), for the current bleeding event prior to enrolment (antifibrinolytic drugs and local haemostatic agents are allowed)
• Patients who received clopidogrel within 5 days or prasugrel within 7 days or ticagrelor within the 48 hours preceding the bleeding event
• Patients on enoxaparin therapy for thromboembolic prophylaxis
• A score of less than 7 on the Glasgow Coma Scale or an estimated intracerebral haematoma volume of more than 60 mL
• Patients with expected survival of less than 3 days
• Patients scheduled to undergo surgery in less than 12 hours, with the exception of some minor/invasive procedures that are allowed for diagnostic or therapeutic reasons (see Section 4.1.2)
• Patients who are pregnant or breastfeeding at the time of enrolment
• Patients previously enrolled in this study
• Patients participating in another interventional clinical treatment study currently or during the past 1 month prior to study inclusion |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients in whom OCTAPLEX demonstrates haemostatic effectiveness, i.e., binary outcome of effective (rating of excellent or good) or non-effective (rating of poor/none) in management of major bleeding events. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within 24 hours after the start of initial management, as assessed by the Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to predefined criteria (Section 7.2 of the protocol). |
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E.5.2 | Secondary end point(s) |
• Change in endogenous thrombin potential (ETP) as measured by thrombin generation assay (TGA) from baseline to 1 hour after OCTAPLEX administration
• 30-day event rate of thromboembolic events (TEEs) and all-cause mortality
• Occurrence of adverse events (AEs) during the 48-hour follow up period after OCTAPLEX administration
• Vital signs and laboratory parameters during the 48-hour follow up period after OCTAPLEX administration |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to 30 days after infusion. |
|
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Same study drug with different dose |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Ukraine |
United States |
Austria |
Belgium |
France |
Germany |
Netherlands |
Poland |
Spain |
United Kingdom |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |