Clinical trial NCT04286438: Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemorrhage
Urgent Surgery
Invasive Procedure
Keywords: Bleeding
Lead sponsor: SFJ Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-02-27
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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)

Primary outcomes:
measure: Reversal - Platelet Reactivity Units (PRU)
timeFrame: 4 hours post-initiation of infusion
measure: Hemostasis - Uncontrolled major of life-threatening bleeding - Achievement
timeFrame: 4 hours post-initiation of infusion
measure: Hemostasis - Urgent surgery or invasive procedure - Achievement
timeFrame: 4 hours post-initiation of infusion
Secondary outcomes:
measure: Minimum % inhibition of Platelet Reactivity Index (PRI) (VASP)
timeFrame: 4 hours post-initiation of infusion
measure: Maximum reversal of PRU assessed by VerifyNow™ PRUTest™
timeFrame: 4 hours post-initiation of infusion
measure: Maximum reversal of PRI assessed by VASP
timeFrame: 4 hours post-initiation of infusion
measure: Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 60%
timeFrame: 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)
measure: Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 80%
timeFrame: 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)
measure: Proportion of subjects achieving reversal of platelet inhibition of ticagrelor using PRU and PRI - 100%
timeFrame: 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)
measure: Duration of at least 60% reversal by PRU and PRI
timeFrame: 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)
measure: Duration of at least 80% reversal by PRU and PRI
timeFrame: 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)
measure: Duration of at least 100% reversal by PRU and PRI
timeFrame: 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)
measure: 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)
timeFrame: [Time Frame: Pre-dose, Day 35 and Day 90]
measure: 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)
timeFrame: [Time Frame: Pre-dose, Day 35 and Day 90]
measure: 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)
timeFrame: [Time Frame: Pre-dose, Day 35 and Day 90]
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: University of Florida Health, Jacksonville
state: Florida
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: North Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Springfield
country: United States
facility: Cox Medical Centers
state: Missouri
city: Fargo
country: United States
facility: Sanford Medical Center Fargo
state: North Dakota
city: Tulsa
country: United States
facility: Ascension St. John Clinical Research Institute
state: Oklahoma
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Graz
country: Austria
facility: Medical University Of Graz
state: STY
city: Sankt Pölten
country: Austria
facility: Klinische Abteilung für Innere Medizin 3 Universitätsklinikum St. Pölten
city: Vienna
country: Austria
facility: Klinik Ottakring 3rd Med Dept, Cardiology and Intensive Care Medicine
city: Aalst
country: Belgium
facility: Algemeen Stedelijk Ziekenhuis (ASZ) Study Center Cardiology
state: East Flanders
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg Study Center Intensive Care
state: Limburg
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge-Oostende AV Poli Cardiologie
city: Edegem
country: Belgium
facility: University Hospital Antwerp Cardiology Department - Clinical Trials
city: Hasselt
country: Belgium
facility: Jessa Hospital Hartcentrum Hasselt Research Center
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Etobicoke
country: Canada
facility: William Osler Health System
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Centre
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Science Centre
state: Ontario
city: Newmarket
country: Canada
facility: York PCI Group, Inc.
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital, Unity Health Toronto
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montréal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Beijing
country: China
facility: Beijing Anzhen Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
city: Lanzhou
country: China
facility: Lanzhou University Second Hospital
state: Gansu
city: Guiyang
country: China
facility: Guizhou Provincial People's Hospital
state: Guizhou
city: Harbin
country: China
facility: The First Affiliated Hospital of Harbin Medical University
state: Heilongjiang
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: The Central Hospital of Wuhan
state: Hubei
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
state: Hubei
city: Huai'an
country: China
facility: Huai'an First People's Hospital
state: Jiangsu
city: Suzhou
country: China
facility: First Affiliated Hospital of Soochow University
state: Jiangsu
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Changchun
country: China
facility: The Second Affiliated Hospital of Jilin University
state: Jilin
city: Yinchuan
country: China
facility: General Hospital of Ningxia Medical University
state: Ningxia
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Chest Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Medidata
state: Zhejiang
city: Shanghai
country: China
facility: Shanghai General Hospital
city: Lille Cedex
country: France
facility: CHU de Lille Service USIC, Institut Coeur Poumon
city: Paris
country: France
facility: Assistance Publique-Hopitaux de Paris (AP-HP) Pitie-Salpetriere Hospital
city: Paris
country: France
facility: Bichat Hospital, Service de Cardiologie
city: Tours
country: France
facility: CHRU de Tours - Hopital Trousseau Service de Cardiologie-USCI 2 eme etage
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen gGmbH
city: Monza
country: Italy
facility: ASST Monza - Ospedale San Gerardo
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma Cardiologia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas UO Cardiologia Clinica e Interventistica
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Overijssel
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruna
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre, Residencia general
city: Málaga
country: Spain
facility: Hospital Universitario Vírgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Skane University Hospital, Department of Cardiology
city: Basel
country: Switzerland
facility: Universitatsspital Basel Department of Cardiology
city: Lugano
country: Switzerland
facility: Cardiocentro Ticino
city: Stevenage
country: United Kingdom
facility: East and North Hertfordshire, NHS Trust, Lister Cardiac Research Office, Cardiology Green Zone, Lister Hospital
state: Hertfordshire
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals, NHS Foundation Trust, Northern General Hospital
Study officials:
affiliation: Brigham and Women's Hospital, Division of Cardiovascular Medicine
name: Deepak Bhatt, MD, MPH
role: STUDY_CHAIR
References: