blood and lymphatic system disorders, Uncontrolled Major or Life Threatening Bleeding or Requiring Urgent, Surgery or Invasive Procedure Ticagrelor-Treated Patients with Uncontrolled Bleeding
Conditions
Interventions
This is a multicenter, 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
Sponsors
SFJ Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Male or female > 18 years of age with documented or verbal informed consent. Emergency consent may be obtained where permitted by local regulations and institutional approval. 2. History or documentation of ticagrelor intake within the prior 3 days 3. 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 3 or more days 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 cardiac surgery, neurosurgery, or major orthopedic surgery) • Requires urgent surgery or invasive procedure that 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 elderly patients or patients with underlying cardiac or pulmonary disease who have limited cardiopulmonary reserve)
Exclusion criteria
Exclusion criteria: 1. Known sensitivity or contraindication to PB2452 or any of its excipients 2. 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. 3. Patients expected to be clinically unsalvageable, such as patients with end-stage cancer or patients with overwhelming sepsis. 4. 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 pregnancy may be exclusionary in some regions or countries as directed by national health authorities and/or local IRBs/Ethics Committees 5. Known use of clopidogrel, prasugrel, or ticlopidine within 5 days of study drug administration; known use of antiplatelet GPIIb/IIIa inhibitors, or cangrelor within 5 half-lives of study drug administration; or known use of warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban within 5 half-lives of expected study drug administration 6. Known recent use (< 5 day) of vitamin K, prothrombin complex concentrate, recombinant factor VIIa, idarucizumab, or andexanet-alfa (coagulation factor Xa (recombinant), inactivated-zhzo).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary reversal endpoint: The minimum % inhibition of PRU within 4 hours of the initiation of study drug as assessed by the VerifyNow* PRUTest* platelet function assay. Percent inhibition of PRU is calculated as 100 * [(180 - PRUtrt)/180]. PRUtrt refers to the PRU value measured posttreatment with the study drug. PRU of 180 is considered the lower limit of normal (LLN) platelet function as described in the VerifyNow* PRUTest* manufacturer*s user guidance. Primary hemostasis endpoint: Achievement of effective hemostasis after initiation of PB2452 infusion will be assessed in each population separately and then pooled for primary endpoint analysis. In patients with uncontrolled major bleeding, achievement of effective hemostasis will be assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding adapted from. In patients undergoing urgent surgery or invasive procedure, achievement of effective hemostasis following initiation of PB2452 infusion will be centrally adjudicated using prespecified criteria for effective hemostasis derived from the GUSTO clinical bleeding scale. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints: • Minimum % inhibition of PRI assessed by VASP within 4 hours after the initiation of study drug. Percent inhibition of PRI is calculated as 100 * [(PRIbsl - PRItrt)/ PRIbsl]. PRItrt refers to the PRI value measured posttreatment with the study drug. PRIbsl is the lower limit of normal obtained from previous studies in healthy volunteers • Maximum reversal of PRU assessed by VerifyNow® PRUTest® within 4 hours after the initiation of study drug. Percent reversal is calculated as 100 * [(PRUtrt - PRUpre-trt)/(180- PRUpre-trt)]. PRUpre-trt is defined as the PRU value prior to administration of study drug. PRU of 180 is considered as the lower limit of normal (LLN) for platelet function as described in the VerifyNow® PRUTest® package insert • Maximum reversal of PRI assessed by VASP within 4 hours after the initiation of study drug. Percent reversal is calculated as 100 * [(PRItrt - PRIpre-trt)/(LLN - PRIpre-trt)]. PRIpre-trt is defined as the PRU value prior to administration of study drug. LLN of PRI is obtained from previous studies in healthy volunteers • Proportion of subjects achieving 60%, 80% or 100% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period • Duration of at least 60%, 80%, and 100% reversal by PRU and PRI | — |
Countries
Netherlands
Outcome results
None listed