Primary objectives: • To demonstrate reversal of the antiplatelet effects of ticagrelor after initiation of the intravenous (IV) infusion of PB2452 using the VerifyNow* PRUTest* (VerifyNow*, 2016) platelet function assay in ticagrelor-treated…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
blood and lymphatic system disorders, Uncontrolled Major or Life Threatening Bleeding or Requiring Urgent, Surgery or Invasive Procedure
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
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
Background summary
PB2452 is a specific and selective neutralizing antibody fragment that binds
ticagrelor and TAM, the major active circulating ticagrelor metabolite, with
high affinity and selectivity. PB2452 is intended to reverse the antiplatelet
effects of ticagrelor in patients who experience uncontrolled major or
life-threatening bleeding or who require urgent surgery or invasive procedure,
serious but rare conditions that represent an unmet medical need.
(reference IB section 2: Introduction)
Study objective
Primary objectives:
• To demonstrate reversal of the antiplatelet effects of ticagrelor after
initiation of the intravenous (IV) infusion of PB2452 using the VerifyNow*
PRUTest* (VerifyNow*, 2016) platelet function assay in ticagrelor-treated
patients presenting with uncontrolled major or life-threatening bleeding or
requiring urgent surgery or invasive procedure.
• To demonstrate the effect of PB2452 on achievement of effective hemostasis
after administration of PB2452 in ticagrelor-treated patients presenting with
uncontrolled major or life-threatening bleeding or requiring urgent surgery or
invasive procedure
Secondary objective:
• To demonstrate reversal of the antiplatelet effects of ticagrelor with
intravenous (IV) infusion of PB2452 by measurement of the platelet reactivity
index (PRI) using the vasodilator-stimulated phosphoprotein (VASP) assay in
addition to PRU in ticagrelor-treated patients presenting with uncontrolled
major or life-threatening bleeding or requiring urgent surgery or invasive
procedure.
Study design
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 bleeding or who require urgent surgery
or invasive procedure. Approximately 200 patients will be enrolled from
approximately 200 centers in North America, Europe, and Asia-Pacific regions,
including mainland China. Patients with reported use of ticagrelor within the
prior 3 days who require urgent ticagrelor reversal will be eligible for
enrollment.
Study drug will be administered as 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. The total
infusion time of PB2452 will be 16 hours and 10 minutes, and total volume,
approximately 180 mL. The dose will be adjusted for patients with known
concomitant use of a moderate or strong CYP3A inhibitor.
(see protocol synopsis for more details).
Intervention
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 bleeding or who require urgent surgery
or invasive procedure.
Study drug will be administered as 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.
Study burden and risks
PB2452 has been shown to provide immediate and sustained reversal of the
antiplatelet effects of ticagrelor in early phase studies. In this Phase 3
study, this rapid and sustained reversal of ticagrelor by PB2452 is expected to
provide clinically meaningful and potentially life-saving benefit to enrolled
patients taking ticagrelor who present with uncontrolled major or
life-threatening bleeding or who are in need of urgent surgery by supporting
rapid hemostasis or prevention of procedure-related bleeding. The risks related
to PB2452 administration are expected to be low and infrequent.
Refer to IB (6.5.2.4 Overall benefit-risk summary)
Based on all available information concerning the potential benefits and risks
of PB2452, the absence of alternative therapies for the target patient
populations, and the precautions included in this clinical study, the risks are
considered acceptable to enroll ticagrelor-treated patients who present with
uncontrolled major or life-threatening bleeding or who require urgent surgery
or invasive procedure.
5000 Hopyard Road Suite 330
Pleasanton, CA 94588
US
5000 Hopyard Road Suite 330
Pleasanton, CA 94588
US
Listed location countries
Age
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
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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004457-92-NL |
| ClinicalTrials.gov | NCT04286438 |
| CCMO | NL75256.100.20 |