Evaluation of Four-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitor-Associated Major Bleeding in Patients on DOAC Therapy
- Trial ID
- 2024-515485-14-00
- Protocol
- LEX-210
- Sponsor
- Octapharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superior **haemostatic** effectiveness of OCTAPLEX, a four-factor prothrombin complex concentrate, when dosed at 50 IU/Kg body weight compared to 15 IU/Kg body weight. This is aimed at the emergency reversal of the anticoagulant effect of direct oral anticoagulants (DOACs) in patients experiencing major bleeding associated with factor Xa inhibition. The clinical relevance of this objective lies in its potential to improve outcomes in acute major bleeding scenarios by optimizing the dosage of OCTAPLEX for effective and rapid reversal of anticoagulation, thereby reducing morbidity and mortality.
Secondary objectives include:
- Evaluating the effect of OCTAPLEX on **thrombin** generation in patients with acute major bleeding on DOAC therapy with a factor Xa inhibitor.
- Assessing the safety of OCTAPLEX in this patient population.
Participants
The clinical trial involves a total of **170 participants** who are receiving direct oral anticoagulant (DOAC) therapy with a factor Xa inhibitor and are experiencing **acute major bleeding**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their current use of oral factor Xa inhibitors and a known or suspected baseline anti-factor Xa activity of at least 100 ng/mL. The trial includes individuals who have given written informed consent or for whom consent has been obtained from a legally authorized representative. The study population is characterized by the presence of life-threatening or uncontrolled bleeding, symptomatic bleeding in critical organs, or acute overt bleeding associated with a significant drop in hemoglobin levels. The trial does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, indicating that the trial may involve individuals with compromised health status or other vulnerabilities.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the haemostatic efficacy and safety of a four-factor prothrombin complex concentrate, OCTAPLEX, in patients experiencing acute major bleeding while on direct oral anticoagulant (DOAC) therapy with a factor Xa inhibitor. The trial will involve a multicenter, prospective, group-sequential, parallel-group, adaptive design. Participants will be randomly assigned in a 1:1 ratio to receive either a low dose of 15 IU/kg or a high dose of 50 IU/kg of OCTAPLEX. The primary objective is to demonstrate the superior haemostatic effectiveness of the high-dose regimen compared to the low-dose regimen for the emergency reversal of the anticoagulant effect of DOACs.
The trial is expected to commence recruitment on October 1, 2021, and conclude by April 5, 2026. The study will include several key visits: an initial **screening** visit to assess eligibility based on inclusion criteria such as age (≥18 years), written informed consent, and the presence of acute major bleeding. Follow-up visits will occur within 48 hours post-administration of OCTAPLEX to monitor for adverse events, changes in vital signs, and laboratory parameters. The end-of-study visit will evaluate the primary endpoint, which is the proportion of patients achieving effective haemostatic control, and secondary endpoints, including changes in endogenous thrombin potential and the 30-day event rate of thromboembolic events and all-cause mortality.
Participant involvement is anticipated to last for the duration of the acute treatment phase and the subsequent follow-up period, totaling approximately 48 hours post-treatment. Conditions that may lead to early termination from the study include withdrawal of consent, occurrence of severe adverse events, or any situation where continued participation is deemed unsafe by the investigator. The trial will adhere to ethical standards, ensuring that informed consent is obtained from all participants or their legally authorized representatives, with provisions for deferred consent where necessary and permissible by local regulations.
Treatment
The clinical trial involves the administration of **Octaplex 500 I.E.** and **Octaplex 1000 I.E.**, both of which are formulated as a **solution for infusion**. These experimental medications are composed of a combination of **human coagulation factors** including Factor IX, Factor VII, Factor II, Factor X, as well as **Protein C** and **Protein S**. The pharmaceutical form is a powder and solvent for the preparation of an infusion solution. The route of administration is via **intravenous infusion**. The dosing regimen for the trial is set at a maximum of 50 IU/Kg body weight per day, with a total maximum dose of 50 IU/Kg. The treatment period is limited to a single day.
In addition to the experimental medications, the study utilizes a **Human Prothrombin Complex** as a non-experimental treatment. This serves as a standard-of-care therapy or comparator treatment within the trial. The administration and dosing schedules are designed to ensure participant compliance, with monitoring mechanisms in place to track adherence to the prescribed regimen. The trial aims to evaluate the haemostatic effectiveness of the experimental medications in patients experiencing acute major bleeding while on direct oral anticoagulant therapy with a factor Xa inhibitor.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the proportion of patients in whom **OCTAPLEX** demonstrates haemostatic effectiveness. This is evaluated as a binary outcome, categorizing the management of major bleeding events as either effective (rated as excellent or good) or non-effective (rated as poor/none).
Secondary endpoints include several measures: the change in endogenous thrombin potential (ETP) as measured by thrombin generation assay (TGA) from baseline to 1 hour after OCTAPLEX administration, the 30-day event rate of thromboembolic events (TEEs) and all-cause mortality, the occurrence of adverse events (AEs) during a 48-hour follow-up period after OCTAPLEX administration, and the monitoring of vital signs and laboratory parameters during the same 48-hour follow-up period.
The trial is designed as a Phase 3, multicentre, prospective, randomised, double-blinded, group-sequential, parallel-group, adaptive study. Patients will be randomized in a 1:1 ratio to receive either a low-dose (15 IU/kg) or a high-dose (50 IU/kg) of OCTAPLEX. The study aims to demonstrate the haemostatic efficacy and safety of the four-factor prothrombin complex concentrate in patients experiencing acute major bleeding while on direct oral anticoagulant (DOAC) therapy with a factor Xa inhibitor.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients on oral factor Xa inhibitor therapy and with known or suspected baseline anti-factor Xa activity of at least 100 ng/mL: Patients who received or who are believed by the investigator to have received a dose of oral factor Xa inhibitor and who have a baseline antifactor Xa activity of at least 100 ng/mL according to the locally available test (e.g., chromogenic assay) performed outside of the study as part of standard of care OR -Patients who received or who are believed by the investigator to have received their latest dose of oral factor Xa inhibitor (e.g., rivaroxaban ≥ 10 mg, apixaban ≥2.5 mg, edoxaban ≥30 mg) ≤8 hours prior to enrolment OR -Patients who received or who are believed by the investigator to have received their latest dose of oral factor Xa inhibitor (e.g., rivaroxaban ≥ 10 mg, apixaban ≥2.5 mg, edoxaban ≥30 mg) >8 hours prior to enrolment or at an unknown time, but for whom the investigator suspects a baseline anti-factor Xa activity of at least 100 ng/mL and assesses that the administration of OCTAPLEX is clinically indicated
- 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 - Wherever possible, prospective written informed consent will be obtained before enrolment from the patient or, if they are incapable of providing it, from their legally authorised representative;- If prospective written informed consent is not possible, deferred consent procedures will be permitted outside the US if approved by the local ethics committee or otherwise permitted under local regulations;- When deferred consent procedures are used outside the US, written informed consent should be obtained from the patient as soon as they recover the capacity to provide it, or otherwise from their legally authorised representative
- Patients who have acute major bleeding defined as follows: - Bleeding that is 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, gastrointestinal ,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
Exclusion Criteria
- 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 bleeding disorder
- Known inhibitors to coagulation factors II, VII, IX, or X; heparininduced, type II thrombocytopenia; or immunoglobulin A (IgA) deficiency with known antibodies against IgA
- Known hypersensitivity to plasma-derived products or heparin
- 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 ticlopidine within 14 days, prasugrel within 7 days, clopidogrel within 5 days, ticagrelor within 5 days , dipyridamole within 1 day or cangrelor within 1 hour preceding the bleeding event
- Patients on enoxaparin therapy for thromboembolic prophylaxis
- A score of less than 7 on the Glasgow Coma Scale in non-intubated patients or an estimated intracerebral haematoma volume of more than 60 mL (Patients intubated or sedated at the time of screening may be enrolled if intubation or sedation were done for non-neurologic reasons)
- Patients with expected survival of less than 24 hours, in the opinion of the investigator (in collaboration with other medical experts as appropriate per usual local practice)
- Patients scheduled to undergo surgery in less than 12 hours, with the exception of minor/surgeries and invasive procedures which are allowed for diagnostic or therapeutic reasons or if intended to address a second (non-index) bleeding event
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Oct 2021 | 15 |
 Croatia | Not Recruiting | 01 Oct 2021 | 15 |
 Germany | Not Recruiting | 01 Oct 2021 | 35 |
 Italy | Not Recruiting | 01 Oct 2021 | 30 |
 Poland | Not Recruiting | 01 Oct 2021 | 40 |
 Spain | Not Recruiting | 01 Oct 2021 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Octaplex 500 I.E. Pulver und Lösungsmittel zur Herstellung einer Infusionslösung | Test | PULVER UND LÖSUNGSMITTEL ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 50 | 1 | PRD311325 |
Octaplex 1000 I.E. Pulver und Lösungsmittel zur Herstellung einer Infusionslösung | Test | PULVER UND LÖSUNGSMITTEL ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 50 | 1 | PRD3260403 |