Overview
This is a multi-center, open-label, prospective single-arm study of reversal of the antiplatelet effects of ticagrelor with PB2452 in patients who present with uncontrolled major or life-threatening bleeding or who require urgent surgery or invasive procedure.
Approximately 200 patients will be enrolled at approximately 200 centers worldwide. Patients with reported use of ticagrelor within the prior 5 days who require urgent ticagrelor reversal will be eligible for enrollment. These populations will be enrolled based on separate inclusion criteria.
Description
The study will consist of a Screening/Pre-treatment period, an on-site assignment to study treatment and administration, a Follow-up visit on (Day 3 and Day 7) and a Final Follow-up visit (Day 35). Infusion of PB2452 will be initiated on Day 1 and will continue for approximately 16 hours for a total of 18 g.
On Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will receive an intravenous (IV) infusion comprised of an initial IV bolus of 6 grams (g) infused over 10 minutes for rapid reversal, followed immediately by a 6g IV loading infusion over 4 hours and then a 6g IV maintenance infusion over 12 hours. This PB2452 regimen is expected to provide immediate reversal of the antiplatelet effects of ticagrelor within 5 minutes of the initiation of infusion that is sustained for 20-24 hours.
In subjects with potential drug interaction from concomitant use of moderate or strong CYP3A inhibitors with ticagrelor, an alternative regimen may be used comprising administration of 36 g over an active treatment period of 24 hours and 10 min. (This alternative regimen will be an initial 12g bolus infusion over 10 minutes, followed immediately by a loading infusion of 12g over 6 hours which will then be followed by a maintenance regimen of 12g infused over 18 hours for a total infusion of 24 hours and 10 minutes).
All subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already discharged, and on Day 35 ( 3 days).
Eligibility
Inclusion Criteria:
- Patients will be eligible for inclusion into the study if they meet all of the
following criteria:
- Male or female >18 years of age with written informed consent form (or emergency consent if applicable)
- History or documentation of ticagrelor intake within the prior 5 days
- Patients described below who require urgent reversal of the antiplatelet effects of ticagrelor:
Patients with uncontrolled major or life-threatening bleeding, requiring urgent reversal of the antiplatelet effects of ticagrelor. It is expected that enrolled patients would have characteristics similar to those described below:
- Potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise, e.g., systolic blood pressure < 90 mm Hg and signs or symptoms of low cardiac output not otherwise explained
- Bleeding in a critical organ or closed space, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular bleed with compartment syndrome
- Visible, uncontrolled bleeding associated with a corrected hemoglobin level < 8.0 g/dL, a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) from a known baseline, or requirement for transfusion of 2 or more units of packed red blood cells (PRBC)
Patients requiring urgent surgery or invasive procedure when it is not medically advisable either to proceed urgently with impaired hemostasis or to delay the urgent procedure for 5 days as directed by ticagrelor labeling due to the high risk of bleeding. These patients may typically be in any of the following clinical situations:
- Requires urgent surgery or invasive procedure known to be associated with a risk of significant bleeding (such as coronary artery bypass graft surgery or neurosurgery)
- Requires urgent surgery or invasive procedure which may have an adverse procedural outcome if hemostasis is impaired (such as neurological, spinal, ophthalmological, urological, or orthopedic surgery)
- At risk of experiencing life-threatening events, such as, shock, myocardial infarction, or stroke, if significant intraoperative or postoperative bleeding occurs such as in patients with significant atherosclerosis.
Exclusion Criteria:
- Known sensitivity or contraindication to PB2452 or any of its excipients
- Patients in whom ticagrelor reversal is not considered urgent, e.g., patients with stable or non-acute conditions who have low hemoglobin due to chronic, low-grade gastrointestinal bleeding or who have stable, remote, or asymptomatic intracranial hemorrhage
- Patients expected to be clinically unsalvageable, such as, patients with intracranial hemorrhage with Glasgow Coma Scale 8, or an intracerebral hematoma volume > 60 cc or patients with overwhelming sepsis
- Any condition which, in the opinion of the investigator, would make it unsafe or unsuitable for the patients to participate in this study. This includes assessment of likelihood to cooperate with study follow-up visits and procedures
- Known recent use (< 5 day) of antithrombotic agents other than aspirin and ticagrelor, e.g., warfarin, clopidogrel, prasugrel, dabigatran, oral factor Xa inhibitors, heparin, low-molecular-weight heparin, or fondaparinux
- Known recent use (< 5 day) of other agents to reverse the effects of antithrombotic agents other than aspirin or ticagrelor, including vitamin K, prothrombin complex concentrates or recombinant factors VIIa, whole blood or plasma transfusions, idarucizumab, or andexanet-alfa (coagulation factor Xa (recombinant), inactivated-zhzo)