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

Hemorrhage Clinical Trial

— REVERSE-IT  

Official title:

A Phase 3, Multicenter, Open-Label, Single-Arm Study of Bentracimab (PB2452) in Ticagrelor-Treated Patients With Uncontrolled Major or Life-Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure (REVERSE-IT Trial)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04286438
• Other study ID #: PB2452-PT-CL-0004
• Secondary ID: 2019-004457-92
• Status: Recruiting
• Phase: Phase 3
• Start date: March 30, 2020
• Est. completion date: August 15, 2024

Study information

• Verified date: December 2023
• Source: SFJ Pharmaceuticals, Inc.
• Contact: Clinical Trials
• Phone: 1-925-223-6233
• Email: pb2452_clinops[@]sfj-pharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: August 15, 2024
• Est. primary completion date: August 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Hemorrhage
• Invasive Procedure
• Urgent Surgery

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Austria	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
Belgium	Algemeen Stedelijk Ziekenhuis (ASZ) Study Center Cardiology	Aalst	East Flanders
Belgium	AZ Sint-Jan Brugge-Oostende AV Poli Cardiologie	Brugge
Belgium	University Hospital Antwerp Cardiology Department - Clinical Trials	Edegem
Belgium	Ziekenhuis Oost-Limburg Study Center Intensive Care	Genk	Limburg
Belgium	Jessa Hospital Hartcentrum Hasselt Research Center	Hasselt
Belgium	University Hospital Leuven, Universitair Ziekenhuis Leuven Dienst Bloedings- en Vaatziekten	Leuven
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hamilton Health Sciences Centre	Hamilton	Ontario
Canada	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	McGill University Health Centre Glen Site	Montréal	Quebec
Canada	Montreal Heart Institute	Montréal	Quebec
Canada	York PCI Group, Inc.	Newmarket	Ontario
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	Institut universitaire de cardiologie et de pneumologie de Quebec - Universite Laval	Quebec
Canada	Saint John Regional Hospital	Saint John	New Brunswick
Canada	St. Michael's Hospital, Unity Health Toronto	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
China	Beijing Anzhen Hospital, Capital Medical University	Beijing	Beijing
China	China-Japan Friendship Hospital	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Peking University People's Hospital	Beijing	Beijing
China	Peking University Third Hospital	Beijing	Beijing
China	The First Hospital of Jilin University	Changchun	Jilin
China	Medidata	Hangzhou	Zhejiang
China	Sir Run Run Shaw Hospital, Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Zhejiang Provincial People's Hospital	Hangzhou	Zhejiang
China	Huai'an First People's Hospital	Huai'an	Jiangsu
China	Lanzhou University Second Hospital	Lanzhou	Gansu
China	First Affiliated Hospital of Soochow University	Suzhou	Jiangsu
China	Tianjin Chest Hospital	Tianjin	Tianjin
China	Tianjin Medical University General Hospital	Tianjin	Tianjin
China	The Central Hospital of Wuhan	Wuhan	Hubei
China	First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi
China	Medidata	Yinchuan	Ningxia
France	CHU de Lille Service USIC, Institut Coeur Poumon	Lille Cedex
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
Germany	Klinikum der Stadt Ludwigshafen gGmbH	Ludwigshafen
Italy	ASST Monza - Ospedale San Gerardo	Monza
Italy	Azienda Ospedaliero-Universitaria di Parma Cardiologia	Parma
Italy	Istituto Clinico Humanitas UO Cardiologia Clinica e Interventistica	Rozzano
Netherlands	Medisch Spectrum Twente	Enschede	Overijssel
Netherlands	St Antonius Hospital	Nieuwegein
Spain	Complejo Hospitalario Universitario A Coruna	A Coruña
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Clinico San Carlos - Instituto Cardiovascular (ICV)	Madrid
Spain	Hospital Universitario 12 de Octubre, Residencia general	Madrid
Spain	Hospital Universitario Vírgen de la Victoria	Málaga
Spain	Hospital Universitario Virgen Macarena	Sevilla
Sweden	Sahlgrenska University Hospital	Göteborg
Sweden	Skane University Hospital, Department of Cardiology	Lund
Sweden	Region Uppsala, Akademiska Hospital Cardio and Pulmonary Medicine and Clinical Physiology	Uppsala
Sweden	Uppsala Clinical Research Center	Uppsala
Switzerland	Universitatsspital Basel Department of Cardiology	Basel
Switzerland	Cardiocentro Ticino	Lugano
United Kingdom	Sheffield Teaching Hospitals, NHS Foundation Trust, Northern General Hospital	Sheffield
United Kingdom	East and North Hertfordshire, NHS Trust, Lister Cardiac Research Office, Cardiology Green Zone, Lister Hospital	Stevenage	Hertfordshire
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Henry Ford Hospital	Detroit	Michigan
United States	Sanford Medical Center Fargo	Fargo	North Dakota
United States	JPS Health Network	Fort Worth	Texas
United States	Providence St. Jude Medical Center	Fullerton	California
United States	Stern Cardiovascular Foundation, Inc.	Germantown	Tennessee
United States	East Carolina University	Greenville	North Carolina
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Baptist Medical Center	Jacksonville	Florida
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Florida Health, Jacksonville	Jacksonville	Florida
United States	Ballad Health Research	Johnson City	Tennessee
United States	University of Kentucky	Lexington	Kentucky
United States	Duke Heart Center at Southeastern Health	Lumberton	North Carolina
United States	North Kansas City Hospital	North Kansas City	Missouri
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Beaumont Hospital, Royal Oak	Royal Oak	Michigan
United States	Ochsner LSU Health Shreveport	Shreveport	Louisiana
United States	White Oak Medical Center	Silver Spring	Maryland
United States	Cox Medical Centers	Springfield	Missouri
United States	Ascension St. John Clinical Research Institute	Tulsa	Oklahoma
United States	Crozer Chester Medical Center	Upland	Pennsylvania
United States	MedStar Health Research Institute	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
SFJ Pharmaceuticals, Inc.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Minimum % inhibition of Platelet Reactivity Index (PRI) (VASP)	Minimum % inhibition of PRI assessed by VASP within 4 hours after the initiation of study drug	4 hours post-initiation of infusion
Secondary	Maximum reversal of PRU assessed by VerifyNow™ PRUTest™	Maximum reversal of PRU assessed by VerifyNow™ PRUTest™ within 4 hours after the initiation of study drug.	4 hours post-initiation of infusion
Secondary	Maximum reversal of PRI assessed by VASP	Maximum reversal of PRI assessed by VASP within 4 hours after the initiation of study drug.	4 hours post-initiation of infusion
Secondary	Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 60%	Proportion of subjects achieving 60% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period	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)
Secondary	Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 80%	Proportion of subjects achieving 80% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period	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)
Secondary	Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 100%	Proportion of subjects achieving 100% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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]
Secondary	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]
Secondary	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]