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

NCT04286438 | Completed Phase 3 DMC FDA Drug

• 2 other identifiers: PB2452-PT-CL-00042019-004457-92
• Study Type: interventional
• Target: 226
• Locations: 13 countries
• Sites: 68

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.

Conditions

Hemorrhage; Urgent Surgery; Invasive Procedure

Keywords

Bleeding

Outcome Measures

Primary Outcomes (3)

• Reversal - Platelet Reactivity Units (PRU)

  Minimum % inhibition of PRU within 4 hours of the initiation of study drug as assessed by VerifyNow™ PRUTest™ platelet function assay

  4 hours post-initiation of infusion

• Hemostasis - Uncontrolled major of life-threatening bleeding - Achievement

  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 \[Scale (from best to worst) measured as: Excellent, Good, Poor/None\]

  4 hours post-initiation of infusion

• Hemostasis - Urgent surgery or invasive procedure - Achievement

  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 \[GUSTO scale (from best to worst): Effective (no bleeding, mild bleeding or moderate bleeding) or Not effective (severe bleeding)\]

  4 hours post-initiation of infusion

Secondary Outcomes (12)

• Minimum % inhibition of Platelet Reactivity Index (PRI) (VASP)

  4 hours post-initiation of infusion

• Maximum reversal of PRU assessed by VerifyNow™ PRUTest™

  4 hours post-initiation of infusion

• Maximum reversal of PRI assessed by VASP

  4 hours post-initiation of infusion

• 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 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)

Study Arms (1)

Bentracimab (PB2452) Infusion - Open Label Active Drug

EXPERIMENTAL

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.

Drug: Bentracimab (PB2452) Infusion

Interventions

Bentracimab (PB2452) Infusion 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.

Bentracimab (PB2452) Infusion - Open Label Active Drug

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• SFJ Pharmaceuticals, Inc.: lead

Study Sites (68)

University of Florida Health, Jacksonville

Jacksonville, Florida, 32209, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

Sinai Hospital of Baltimore

Baltimore, Maryland, 21215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

North Kansas City Hospital

North Kansas City, Missouri, 64116, United States

Location

Cox Medical Centers

Springfield, Missouri, 65807, United States

Location

Sanford Medical Center Fargo

Fargo, North Dakota, 58104, United States

Location

Ascension St. John Clinical Research Institute

Tulsa, Oklahoma, 74104, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Medical University Of Graz

Graz, STY, 8036, Austria

Location

Klinische Abteilung für Innere Medizin 3 Universitätsklinikum St. Pölten

Sankt Pölten, 3100, Austria

Location

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

Vienna, 1160, Austria

Location

Algemeen Stedelijk Ziekenhuis (ASZ) Study Center Cardiology

Aalst, East Flanders, 9300, Belgium

Location

Ziekenhuis Oost-Limburg Study Center Intensive Care

Genk, Limburg, 3600, Belgium

Location

AZ Sint-Jan Brugge-Oostende AV Poli Cardiologie

Bruges, 8000, Belgium

Location

University Hospital Antwerp Cardiology Department - Clinical Trials

Edegem, 2650, Belgium

Location

Jessa Hospital Hartcentrum Hasselt Research Center

Hasselt, 3500, Belgium

Location

Foothills Medical Centre

Calgary, Alberta, T2N 2T9, Canada

Location

Saint John Regional Hospital

Saint John, New Brunswick, E2L 4L2, Canada

Location

William Osler Health System

Etobicoke, Ontario, M9V 1R8, Canada

Location

Hamilton Health Sciences Centre

Hamilton, Ontario, L8L 2X2, Canada

Location

Kingston Health Science Centre

Kingston, Ontario, ON K7L 2V7, Canada

Location

York PCI Group, Inc.

Newmarket, Ontario, L3Y 2P7, Canada

Location

St. Michael's Hospital, Unity Health Toronto

Toronto, Ontario, M5B 1W8, Canada

Location

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

Montreal Heart Institute

Montreal, Quebec, H1T 1C8, Canada

Location

Beijing Anzhen Hospital, Capital Medical University

Beijing, Beijing Municipality, 100029, China

Location

Peking University First Hospital

Beijing, Beijing Municipality, 100034, China

Location

Peking University People's Hospital

Beijing, Beijing Municipality, 100044, China

Location

Peking University Third Hospital

Beijing, Beijing Municipality, 100083, China

Location

Lanzhou University Second Hospital

Lanzhou, Gansu, 730030, China

Location

Guizhou Provincial People's Hospital

Guiyang, Guizhou, 550002, China

Location

The First Affiliated Hospital of Harbin Medical University

Harbin, Heilongjiang, 150001, China

Location

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, 45000, China

Location

The Central Hospital of Wuhan

Wuhan, Hubei, 430014, China

Location

Renmin Hospital of Wuhan University

Wuhan, Hubei, 430060, China

Location

Huai'an First People's Hospital

Huai'an, Jiangsu, 223300, China

Location

First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, 215031, China

Location

The Second Affiliated Hospital of Nanchang University

Nanchang, Jiangxi, 330006, China

Location

The First Hospital of Jilin University

Changchun, Jilin, 130021, China

Location

The Second Affiliated Hospital of Jilin University

Changchun, Jilin, 130041, China

Location

General Hospital of Ningxia Medical University

Yinchuan, Ningxia, 750004, China

Location

Tianjin Medical University General Hospital

Tianjin, Tianjin Municipality, 300052, China

Location

Tianjin Chest Hospital

Tianjin, Tianjin Municipality, 300222, China

Location

Sir Run Run Shaw Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, 310000, China

Location

Medidata

Hangzhou, Zhejiang, 310009, China

Location

Shanghai General Hospital

Shanghai, 200080, China

Location

CHU de Lille Service USIC, Institut Coeur Poumon

Lille, 59037, France

Location

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

Paris, 75013, France

Location

Bichat Hospital, Service de Cardiologie

Paris, 75018, France

Location

CHRU de Tours - Hopital Trousseau Service de Cardiologie-USCI 2 eme etage

Tours, 37170, France

Location

Klinikum der Stadt Ludwigshafen gGmbH

Ludwigshafen, 67063, Germany

Location

ASST Monza - Ospedale San Gerardo

Monza, 20090, Italy

Location

Azienda Ospedaliero-Universitaria di Parma Cardiologia

Parma, 43126, Italy

Location

Istituto Clinico Humanitas UO Cardiologia Clinica e Interventistica

Rozzano, 20089, Italy

Location

Medisch Spectrum Twente

Enschede, Overijssel, 7512 KZ, Netherlands

Location

St Antonius Hospital

Nieuwegein, 3435 CM, Netherlands

Location

Complejo Hospitalario Universitario A Coruna

A Coruña, 15006, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario 12 de Octubre, Residencia general

Madrid, 28007, Spain

Location

Hospital Universitario Vírgen de la Victoria

Málaga, 28040, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Sahlgrenska University Hospital

Gothenburg, 413 45, Sweden

Location

Skane University Hospital, Department of Cardiology

Lund, 22185, Sweden

Location

Universitatsspital Basel Department of Cardiology

Basel, 4031, Switzerland

Location

Cardiocentro Ticino

Lugano, 6900, Switzerland

Location

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

Stevenage, Hertfordshire, SG1 4AB, United Kingdom

Location

Sheffield Teaching Hospitals, NHS Foundation Trust, Northern General Hospital

Sheffield, S5 7AU, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 38319214 DERIVED

MeSH Terms

Conditions

Hemorrhage

Interventions

PB-2452

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Deepak Bhatt, MD, MPH

  Brigham and Women's Hospital, Division of Cardiovascular Medicine

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2020
• First Posted: February 27, 2020
• Study Start: July 15, 2020
• Primary Completion: September 9, 2024
• Study Completion: September 9, 2024
• Last Updated: October 21, 2024

Record last verified: 2024-10

Locations

FR (4); GB (2); NL (2); IT (3); ES (5); DE (1); AU (3); CN (21); BE (5); CH (2); US (9); SE (2); CA (9)