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PB2452 in Ticagrelor-treated Patients With Uncontrolled Major or Life-Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure

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ClinicalTrials.gov Identifier: NCT04286438
Recruitment Status : Recruiting
First Posted : February 27, 2020
Last Update Posted : April 10, 2020
Sponsor:
Information provided by (Responsible Party):
PhaseBio Pharmaceuticals Inc.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Hemorrhage Urgent Surgery Invasive Procedure Drug: PB2452 Infusion Phase 3

Detailed 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Open-Label, Single-Arm Study of PB2452 in Ticagrelor-Treated Patients With Uncontrolled Major or Life-Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure
Actual Study Start Date : March 27, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding
Drug Information available for: Ticagrelor

Arm Intervention/treatment
Experimental: PB2452 Injection - Open Label Active Drug

PB2452 18 g Intravenous Infusion over a 16 hour duration. Patients with uncontrolled major or life-threatening bleeding.

PB2452 18 g Intravenous Infusion over a 16 hour duration. For patients in need of urgent surgery or invasive procedure.

Drug: PB2452 Infusion

PB2452 18 g Intravenous Infusion over a 16 hour duration.

In subjects with potential drug interaction from concomitant use of moderate or strong CYP3A inhibitors with ticagrelor, the active treatment period may be 24 hours and 10 min if receiving the 36g infusion





Primary Outcome Measures :
  1. Reversal - Platelet Reactivity Units (PRU) [ Time Frame: 4 hours post-initiation of infusion ]
    Minimum % inhibition of PRU within 4 hours of the initiation of study drug as assessed by VerifyNow® PRUTest® platelet function assay

  2. Hemostasis - Major of life-threatening bleeding - Achievement [ Time Frame: 4 hours post-initiation of infusion ]
    Achievement of effective (graded as good or excellent) hemostasis from the initiation of infusion will be assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding [Scale (from best to worst) measured as: Excellent, Good, Poor/None]

  3. Hemostasis - Major of life-threatening bleeding - Time [ Time Frame: Any time point between dosing to 4 hours post-initiation of infusion ]
    Time to good or excellent hemostasis from the initiation of infusion will be assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding [Scale (from best to worst) measured as: Excellent, Good, Poor/None]

  4. Hemostasis - Urgent surgery or invasive procedure [ Time Frame: 4 hours post-initiation of infusion ]
    Achievement of effective hemostasis will be assessed using prespecified criteria for effective hemostasis derived from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) clinical bleeding scale [GUSTO scale (from best to worst): Effective (no bleeding, mild bleeding or moderate bleeding) or Not effective (severe bleeding)]


Secondary Outcome Measures :
  1. Minimum % inhibition of Platelet Reactivity Index (PRI) (VASP) [ Time Frame: 4 hours post-initiation of infusion ]
    Minimum % inhibition of PRI assessed by VASP within 4 hours after the initiation of study drug

  2. Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 60% [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]
    Proportion of subjects achieving 60% reversal of platelet inhibition of ticagrelor using PRU and PRI at any time point during the treatment period

  3. Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 80% [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]
    Proportion of subjects achieving 80% reversal of platelet inhibition of ticagrelor using PRU and PRI at any time point during the treatment period

  4. Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 100% [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]
    Proportion of subjects achieving 100% reversal of platelet inhibition of ticagrelor using PRU and PRI at any time point during the treatment period

  5. Duration of at least 60% reversal by PRU and PRI [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]
  6. Duration of at least 80% reversal by PRU and PRI [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]
  7. Duration of at least 100% reversal by PRU and PRI [ Time Frame: Any time point between infusion initiation and day 3 (Pre-dose, 5-10 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, 24 hours, and Day 3) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients will be eligible for inclusion into the study if they meet all of the following criteria:

    1. Male or female >18 years of age with written informed consent form (or emergency consent if applicable)
    2. History or documentation of ticagrelor intake within the prior 5 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 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:

  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 intracranial hemorrhage with Glasgow Coma Scale ≤ 8, or an intracerebral hematoma volume > 60 cc 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
  5. 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
  6. 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04286438


Contacts
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Contact: Clinical Trials 888-521-2805 Clinicaltrials@phasebio.com

Locations
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United States, District of Columbia
MedStar Health Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Contact: Terry Moriarty, MSN, RN, CCRC    202-877-3657    Theresa.m.moriarty@medstar.net   
Principal Investigator: Munish Goyal, MD         
United States, Maryland
White Oak Medical Center Recruiting
Silver Spring, Maryland, United States, 20904
Contact: Anthony Rongione, MD    202-524-4200    arongione@verizon.net   
Principal Investigator: Anthony Rongione, MD         
Sponsors and Collaborators
PhaseBio Pharmaceuticals Inc.
Investigators
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Study Chair: Deepak Bhatt, MD, MPH Brigham and Women's Hospital, Division of Cardiovascular Medicine

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Responsible Party: PhaseBio Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT04286438    
Other Study ID Numbers: PB2452-PT-CL-0004
First Posted: February 27, 2020    Key Record Dates
Last Update Posted: April 10, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PhaseBio Pharmaceuticals Inc.:
Bleeding
Additional relevant MeSH terms:
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Hemorrhage
Pathologic Processes