Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure
- Conditions
- HemorrhageUrgent SurgeryInvasive Procedure
- Interventions
- Registration Number
- NCT04286438
- Lead Sponsor
- SFJ Pharmaceuticals, Inc.
- Brief Summary
This is a multi-center, open-label, prospective single-arm study of reversal of the antiplatelet effects of ticagrelor with bentracimab (PB2452) in patients who present with uncontrolled major or life-threatening bleeding or who require urgent surgery or invasive procedure.
At least 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. These populations will be enrolled based on separate inclusion criteria.
- 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+1 and Day 7±1), a Final Follow-up visit (Day 35±3) and a Follow-up visit for intracranial hemorrhage (ICH) only patients (Day 90±10). 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 6 g IV maintenance infusion over 12 hours. This bentracimab (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 recent 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 12 g bolus infusion over 10 minutes, followed immediately by a loading infusion of 12 g over 6 hours which will then be followed by a maintenance regimen of 12 g infused over 18 hours for a total infusion of 36 grams over 24 hours and 10 minutes).
In patients presenting with intracranial hemorrhage (ICH), brain imaging within 2 hours of initiation of study drug and at least one follow-up brain imaging performed 12-24 hours post completion of PB2452 will be required to support adjudication of hemostasis.
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). All ICH patients must complete End of Study (EOS) Day 35±3 (Visit 5). ICH patients that agree to participate in the ICH-only-90-day-follow-up visit will have an additional visit on Day 90±10 (Visit 6).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 226
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 documented or verbal informed consent. Emergency consent may be obtained where permitted by local regulations and institutional approval.
- History or documentation of ticagrelor intake within the prior 3 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 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)
- 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 end-stage cancer 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 pregnancy may be exclusionary in some regions or countries as directed by national health authorities and/or local Institutional Review Boards/Ethics Committees
- 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 expected study drug administration; or known use of warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban within 5 half-lives of expected study drug administration
- Known recent use (< 5 day) of vitamin K, prothrombin complex concentrate, recombinant factor VIIa, idarucizumab, or andexanet-alfa (coagulation factor Xa (recombinant), inactivated-zhzo)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Bentracimab (PB2452) Infusion - Open Label Active Drug Bentracimab (PB2452) Infusion Bentracimab (PB2452) 18 g Intravenous Infusion over a 16 hour duration. For patients with uncontrolled major or life-threatening bleeding or in need of urgent surgery or invasive procedure.
- Primary Outcome Measures
Name Time Method Hemostasis - Urgent surgery or invasive procedure - Achievement 4 hours post-initiation of infusion Achievement of effective hemostasis following initiation of PB2452 infusion will be centrally adjudicated using prespecified criteria for effective hemostasis derived from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) clinical bleeding scale \[GUSTO scale (from best to worst): Effective (no bleeding, mild bleeding or moderate bleeding) or Not effective (severe bleeding)\]
Reversal - Platelet Reactivity Units (PRU) 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
Hemostasis - Uncontrolled major of life-threatening bleeding - Achievement 4 hours post-initiation of infusion Achievement of effective (graded as good or excellent) hemostasis after initiation of PB2452 infusion will be assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding \[Scale (from best to worst) measured as: Excellent, Good, Poor/None\]
- Secondary Outcome Measures
Name Time Method Minimum % inhibition of Platelet Reactivity Index (PRI) (VASP) 4 hours post-initiation of infusion Minimum % inhibition of PRI assessed by VASP within 4 hours after the initiation of study drug
Maximum reversal of PRI assessed by VASP 4 hours post-initiation of infusion Maximum reversal of PRI assessed by VASP within 4 hours after the initiation of study drug.
Duration of at least 100% reversal by PRU and PRI Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) Intracranial hemorrhage (ICH) Patients Only: Proportion of ICH patients with modified Rankin Scale (mRS) score of 0-3 versus 4-6 at 90 days on a scale of 0-6 (better to worse) [Time Frame: Pre-dose, Day 35 and Day 90] Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 80% Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) Proportion of subjects achieving 80% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period
Duration of at least 80% reversal by PRU and PRI Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) ICH Patients Only: Absolute and percent change form baseline in modified Rankin Scale (mRS) score at 90 days in ICH patients on a scale of 0-6 (better to worse) [Time Frame: Pre-dose, Day 35 and Day 90] Maximum reversal of PRU assessed by VerifyNow™ PRUTest™ 4 hours post-initiation of infusion Maximum reversal of PRU assessed by VerifyNow™ PRUTest™ within 4 hours after the initiation of study drug.
Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 60% Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) Proportion of subjects achieving 60% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period
Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 100% Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) Proportion of subjects achieving 100% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period
Duration of at least 60% reversal by PRU and PRI Any time point between infusion initiation and Day 3 (Pre-dose, 5-10 minutes, 30+5 minutes, 1+0.25 hours, 4+0.25 hours, 12+0.5 hours, 24+1 hours, and Day 3) ICH Patients Only: EQ-5D 5L Quality of Life Questionnaire index at 90 days and change from baseline in ICH patients on a scale of 0-100 (best to worst) [Time Frame: Pre-dose, Day 35 and Day 90]
Trial Locations
- Locations (101)
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Medisch Spectrum Twente
🇳🇱Enschede, Overijssel, Netherlands
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Intercoastal Medical Group
🇺🇸Sarasota, Florida, United States
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
St. Paul's Hospital (Site # 079)
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
St. Boniface Hospital Inc.
🇨🇦St. Boniface, Manitoba, Canada
William Osler Health System
🇨🇦Etobicoke, Ontario, Canada
Oakville Trafalgar Memorial Hospital
🇨🇦Oakville, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontatio, Canada
The First Affiliated Hospital of Zhengzhou University
🇨🇳Zhengzhou, Henan, China
Renmin Hospital of Wuhan University
🇨🇳Wuhan, Hubei, China
The Second Affiliated Hospital of Nanchang University
🇨🇳Nanchang, Jiangxi, China
The Second Affiliated Hospital of Jilin University
🇨🇳Changchun, Jilin, China
General Hospital of Ningxia Medical University
🇨🇳Yinchuan, Ningxia, China
Guizhou Provincial People's Hospital
🇨🇳Guiyang, Guizhou, China
The First Affiliated Hospital of Harbin Medical University
🇨🇳Harbin, Heilongjiang, China
Shanghai General Hospital
🇨🇳Shanghai, China
Baptist Medical Center
🇺🇸Jacksonville, Florida, United States
University of Florida Health, Jacksonville
🇺🇸Jacksonville, Florida, United States
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Providence St. Jude Medical Center
🇺🇸Fullerton, California, United States
MedStar Health Research Institute
🇺🇸Washington, District of Columbia, United States
White Oak Medical Center
🇺🇸Silver Spring, Maryland, United States
Duke Heart Center at Southeastern Health
🇺🇸Lumberton, North Carolina, United States
North Kansas City Hospital
🇺🇸North Kansas City, Missouri, United States
Beaumont Hospital, Royal Oak
🇺🇸Royal Oak, Michigan, United States
Crozer Chester Medical Center
🇺🇸Upland, Pennsylvania, United States
Stern Cardiovascular Foundation, Inc.
🇺🇸Germantown, Tennessee, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Ballad Health Research
🇺🇸Johnson City, Tennessee, United States
Medical University Of Graz
🇦🇹Graz, STY, Austria
Klinische Abteilung für Innere Medizin 3 Universitätsklinikum St. Pölten
🇦🇹Sankt Pölten, Austria
JPS Health Network
🇺🇸Fort Worth, Texas, United States
Algemeen Stedelijk Ziekenhuis (ASZ) Study Center Cardiology
🇧🇪Aalst, East Flanders, Belgium
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
AZ Sint-Jan Brugge-Oostende AV Poli Cardiologie
🇧🇪Brugge, Belgium
University Hospital Leuven, Universitair Ziekenhuis Leuven Dienst Bloedings- en Vaatziekten
🇧🇪Leuven, Belgium
Klinik Ottakring 3rd Med Dept, Cardiology and Intensive Care Medicine
🇦🇹Vienna, Austria
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada
Hamilton Health Sciences Centre
🇨🇦Hamilton, Ontario, Canada
St. Michael's Hospital, Unity Health Toronto
🇨🇦Toronto, Ontario, Canada
McGill University Health Centre Glen Site
🇨🇦Montréal, Quebec, Canada
Montreal Heart Institute
🇨🇦Montréal, Quebec, Canada
Peking University Third Hospital
🇨🇳Beijing, Beijing, China
Centre intégré universitaire de santé et de services sociaux du Nord-de-l'lle-de-Montréal (CIUSSS NIM)/Hopital du Sacré-Coeur-de-Montréal
🇨🇦Montréal, Quebec, Canada
Beijing Anzhen Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval
🇨🇦Quebec, Canada
China-Japan Friendship Hospital
🇨🇳Beijing, Beijing, China
Peking University First Hospital
🇨🇳Beijing, Beijing, China
Peking University People's Hospital
🇨🇳Beijing, Beijing, China
Lanzhou University Second Hospital
🇨🇳Lanzhou, Gansu, China
First Affiliated Hospital of Soochow University
🇨🇳Suzhou, Jiangsu, China
The First Hospital of Jilin University
🇨🇳Changchun, Jilin, China
First Affiliated Hospital of Xi'an Jiaotong University
🇨🇳Xi'an, Shaanxi, China
The Central Hospital of Wuhan
🇨🇳Wuhan, Hubei, China
Huai'an First People's Hospital
🇨🇳Huai'an, Jiangsu, China
Tianjin Medical University General Hospital
🇨🇳Tianjin, Tianjin, China
Tianjin Chest Hospital
🇨🇳Tianjin, Tianjin, China
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
🇨🇳Hangzhou, Zhejiang, China
Azienda Ospedaliero-Universitaria di Parma Cardiologia
🇮🇹Parma, Italy
Assistance Publique-Hopitaux de Paris (AP-HP) Pitie-Salpetriere Hospital
🇫🇷Paris, France
Istituto Clinico Humanitas UO Cardiologia Clinica e Interventistica
🇮🇹Rozzano, Italy
CHU de Lille Service USIC, Institut Coeur Poumon
🇫🇷Lille Cedex, France
Bichat Hospital, Service de Cardiologie
🇫🇷Paris, France
Zhejiang Provincial People's Hospital
🇨🇳Hangzhou, Zhejiang, China
CHRU de Tours - Hopital Trousseau Service de Cardiologie-USCI 2 eme etage
🇫🇷Tours, France
Klinikum der Stadt Ludwigshafen gGmbH
🇩🇪Ludwigshafen, Germany
ASST Monza - Ospedale San Gerardo
🇮🇹Monza, Italy
St Antonius Hospital
🇳🇱Nieuwegein, Netherlands
Complejo Hospitalario Universitario A Coruna
🇪🇸A Coruña, Spain
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario 12 de Octubre, Residencia general
🇪🇸Madrid, Spain
Hospital Universitario Vírgen de la Victoria
🇪🇸Málaga, Spain
Skane University Hospital, Department of Cardiology
🇸🇪Lund, Sweden
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Sahlgrenska University Hospital
🇸🇪Göteborg, Sweden
East and North Hertfordshire, NHS Trust, Lister Cardiac Research Office, Cardiology Green Zone, Lister Hospital
🇬🇧Stevenage, Hertfordshire, United Kingdom
Uppsala Clinical Research Center
🇸🇪Uppsala, Sweden
Universitatsspital Basel Department of Cardiology
🇨🇭Basel, Switzerland
Cardiocentro Ticino
🇨🇭Lugano, Switzerland
Sheffield Teaching Hospitals, NHS Foundation Trust, Northern General Hospital
🇬🇧Sheffield, United Kingdom
Kingston Health Science Centre
🇨🇦Kingston, Ontario, Canada
University of Tennessee Medical Center
🇺🇸Knoxville, Tennessee, United States
Ochsner LSU Health Shreveport
🇺🇸Shreveport, Louisiana, United States
Cox Medical Centers
🇺🇸Springfield, Missouri, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Hospital Clinico San Carlos - Instituto Cardiovascular (ICV)
🇪🇸Madrid, Spain
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Medidata
🇨🇳Hangzhou, Zhejiang, China
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Sanford Medical Center Fargo
🇺🇸Fargo, North Dakota, United States
Ascension St. John Clinical Research Institute
🇺🇸Tulsa, Oklahoma, United States
Ziekenhuis Oost-Limburg Study Center Intensive Care
🇧🇪Genk, Limburg, Belgium
University Hospital Antwerp Cardiology Department - Clinical Trials
🇧🇪Edegem, Belgium
Jessa Hospital Hartcentrum Hasselt Research Center
🇧🇪Hasselt, Belgium
Saint John Regional Hospital
🇨🇦Saint John, New Brunswick, Canada
York PCI Group, Inc.
🇨🇦Newmarket, Ontario, Canada