Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure

NCT ID: NCT04286438

Last Updated: 2024-10-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 226 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-15
• Study Completion Date: 2024-09-09

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).

Conditions

Hemorrhage; Urgent Surgery; Invasive Procedure

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bentracimab (PB2452) Infusion - Open Label Active Drug

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.

Group Type: EXPERIMENTAL

Bentracimab (PB2452) Infusion

Intervention Type: DRUG

Bentracimab (PB2452) 18 g Intravenous Infusion over a 16 hour duration.

In subjects with potential drug interaction from recent 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.

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.

Interventions

Bentracimab (PB2452) Infusion

Bentracimab (PB2452) 18 g Intravenous Infusion over a 16 hour duration.

In subjects with potential drug interaction from recent 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.

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.

Intervention Type: DRUG

Eligibility 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 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 Institutional Review Boards/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 expected 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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

SFJ Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Deepak Bhatt, MD, MPH

Role: STUDY_CHAIR

Brigham and Women's Hospital, Division of Cardiovascular Medicine

Locations

University of Florida Health, Jacksonville

Jacksonville, Florida, United States

University of Kentucky

Lexington, Kentucky, United States

Sinai Hospital of Baltimore

Baltimore, Maryland, United States

Henry Ford Hospital

Detroit, Michigan, United States

North Kansas City Hospital

North Kansas City, Missouri, United States

Cox Medical Centers

Springfield, Missouri, United States

Sanford Medical Center Fargo

Fargo, North Dakota, United States

Ascension St. John Clinical Research Institute

Tulsa, Oklahoma, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Medical University Of Graz

Graz, STY, Austria

Klinische Abteilung für Innere Medizin 3 Universitätsklinikum St. Pölten

Sankt Pölten, , Austria

Klinik Ottakring 3rd Med Dept, Cardiology and Intensive Care Medicine

Vienna, , Austria

Algemeen Stedelijk Ziekenhuis (ASZ) Study Center Cardiology

Aalst, East Flanders, Belgium

Ziekenhuis Oost-Limburg Study Center Intensive Care

Genk, Limburg, Belgium

AZ Sint-Jan Brugge-Oostende AV Poli Cardiologie

Bruges, , Belgium

University Hospital Antwerp Cardiology Department - Clinical Trials

Edegem, , Belgium

Jessa Hospital Hartcentrum Hasselt Research Center

Hasselt, , Belgium

Foothills Medical Centre

Calgary, Alberta, Canada

Saint John Regional Hospital

Saint John, New Brunswick, Canada

William Osler Health System

Etobicoke, Ontario, Canada

Hamilton Health Sciences Centre

Hamilton, Ontario, Canada

Kingston Health Science Centre

Kingston, Ontario, Canada

York PCI Group, Inc.

Newmarket, Ontario, Canada

St. Michael's Hospital, Unity Health Toronto

Toronto, Ontario, Canada

Toronto General Hospital

Toronto, Ontario, Canada

Montreal Heart Institute

Montreal, Quebec, Canada

Beijing Anzhen Hospital, Capital Medical University

Beijing, Beijing Municipality, China

Peking University First Hospital

Beijing, Beijing Municipality, China

Peking University People's Hospital

Beijing, Beijing Municipality, China

Peking University Third Hospital

Beijing, Beijing Municipality, China

Lanzhou University Second Hospital

Lanzhou, Gansu, China

Guizhou Provincial People's Hospital

Guiyang, Guizhou, China

The First Affiliated Hospital of Harbin Medical University

Harbin, Heilongjiang, China

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, China

The Central Hospital of Wuhan

Wuhan, Hubei, China

Renmin Hospital of Wuhan University

Wuhan, Hubei, China

Huai'an First People's Hospital

Huai'an, Jiangsu, China

First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

The Second Affiliated Hospital of Nanchang University

Nanchang, Jiangxi, China

The First Hospital of Jilin University

Changchun, Jilin, China

The Second Affiliated Hospital of Jilin University

Changchun, Jilin, China

General Hospital of Ningxia Medical University

Yinchuan, Ningxia, China

Tianjin Medical University General Hospital

Tianjin, Tianjin Municipality, China

Tianjin Chest Hospital

Tianjin, Tianjin Municipality, China

Sir Run Run Shaw Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

Medidata

Hangzhou, Zhejiang, China

Shanghai General Hospital

Shanghai, , China

CHU de Lille Service USIC, Institut Coeur Poumon

Lille, , France

Assistance Publique-Hopitaux de Paris (AP-HP) Pitie-Salpetriere Hospital

Paris, , France

Bichat Hospital, Service de Cardiologie

Paris, , France

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

Azienda Ospedaliero-Universitaria di Parma Cardiologia

Parma, , Italy

Istituto Clinico Humanitas UO Cardiologia Clinica e Interventistica

Rozzano, , Italy

Medisch Spectrum Twente

Enschede, Overijssel, Netherlands

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

Hospital Universitario Virgen Macarena

Seville, , Spain

Sahlgrenska University Hospital

Gothenburg, , Sweden

Skane University Hospital, Department of Cardiology

Lund, , Sweden

Universitatsspital Basel Department of Cardiology

Basel, , Switzerland

Cardiocentro Ticino

Lugano, , Switzerland

East and North Hertfordshire, NHS Trust, Lister Cardiac Research Office, Cardiology Green Zone, Lister Hospital

Stevenage, Hertfordshire, United Kingdom

Sheffield Teaching Hospitals, NHS Foundation Trust, Northern General Hospital

Sheffield, , United Kingdom

Countries

United States; Austria; Belgium; Canada; China; France; Germany; Italy; Netherlands; Spain; Sweden; Switzerland; United Kingdom

References

Bhatt DL, Pollack CV, Mazer CD, Angiolillo DJ, Steg PG, James SK, Weitz JI, Ramnath R, Arnold SE, Mays MC, Umstead BR, White B, Hickey LL, Jennings LK, Curry BJ, Lee JS, Verma S. Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery. NEJM Evid. 2022 Mar;1(3):EVIDoa2100047. doi: 10.1056/EVIDoa2100047. Epub 2021 Dec 1.

Reference Type: DERIVED

PMID: 38319214 (View on PubMed)

Other Identifiers

2019-004457-92

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PB2452-PT-CL-0004

Identifier Type: -

Identifier Source: org_study_id