Study of OCTAPLEX in Patients With Acute Major Bleeding on DOAC Therapy With Factor Xa Inhibitor

Study Overview
=================
Brief Summary
-----------------
This is a multicentre, prospective, randomised, double-blinded, group-sequential, parallel-group, adaptive design, phase 3 study to demonstrate the haemostatic efficacy and safety of four-factor prothrombin complex concentrate, OCTAPLEX, in patients with acute major bleeding on DOAC therapy with factor Xa inhibitor. Patients will be randomised 1:1 to either of two study groups: low-dose vs. high-dose OCTAPLEX.

Official Title
-----------------
Study of Four-factor Prothrombin Complex Concentrate, OCTAPLEX, in Patients With Acute Major Bleeding on Direct Oral Anticoagulant (DOAC) Therapy With Factor Xa Inhibitor

Conditions
-----------------
Acute Major Bleeding

Intervention / Treatment
-----------------
* Drug: Octaplex


Participation Criteria
=================
Eligibility Criteria
-----------------
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) 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 bleeding disorder Known inhibitors to coagulation factors II, VII, IX, or X; heparin-induced, type II thrombocytopenia; or immunoglobulin A (IgA) deficiency with known antibodies against IgA 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 ticlopidine within 14 days, prasugrel within 7 days, clopidogrel within 5 days, ticagrelor within 5 days 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 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octaplex Low-dose<br>Participants to receive 1 Octaplex infusion intravenously | Drug: Octaplex<br>* Four-factor prothrombin complex concentrate (4F-PCC)<br>|
| Experimental: Octaplex High-dose<br>Participants to receive 1 Octaplex infusion intravenously | Drug: Octaplex<br>* Four-factor prothrombin complex concentrate (4F-PCC)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemostatic efficacy | Binary outcome of effective (rating of excellent or good) or non-effective (rating of poor/none) in management of major bleeding events as assessed by the Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to predefined criteria | Within 24 hours after the start of initial management | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in endogenous thrombin potential (ETP) | Change in ETP as measured by thrombin generation assay | From baseline to 1 hour after administration of drug | 
| 30-Day thromboembolic events (TEEs) | 30-day event rate of TEEs | 30 days | 
| 30-Day all-cause mortality | 30 day event rate of all cause mortality events | 30 days | 
| Occurrence of adverse events (AEs) | Occurrence of any AEs from start of OCTAPLEX administration until end of study | From start of IMP infusion until Day 30 | 
| Body Temperature | Temperature measured during a 48-hour follow-up period after OCTAPLEX administration and at discharge | From day of IMP infusion until Day 30 | 
| Pulse | Pulse during a 48-hour follow-up period after OCTAPLEX administration and at discharge | From day of IMP infusion until Day 30 | 
| Respiration rate | Respiration rate during a 48-hour follow-up period after OCTAPLEX administration and at discharge | From day of IMP infusion until Day 30 | 
| Blood pressure | Blood pressure during a 48-hour follow-up period after OCTAPLEX administration and at discharge | From day of IMP infusion until Day 30 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Direct Oral Anticoagulant, Factor Xa Inhibitor