Clinical trial NCT03891524: A Study of JNJ-70033093 (BMS-986177) Versus Subcutaneous Enoxaparin in Participants Undergoing Elective Total Knee Replacement Surgery
Official title: A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Arthroplasty, Replacement, Knee
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-03-27
Enrollment: 1242
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine the efficacy of JNJ-70033093 in preventing total venous thromboembolism (VTE) events (proximal and/or distal deep vein thrombosis \[DVT\] \[asymptomatic confirmed by venography assessment or objectively confirmed symptomatic\], nonfatal pulmonary embolism \[PE\], or any death) during the treatment period.

Detailed description: JNJ-70033093 is an oral anticoagulant for prevention and treatment of thromboembolic events (for example, VTE) that binds and inhibits activated form of human coagulation Factor XI (FXIa) with high affinity and selectivity. The study will consist of 3 phases: up to 30-day screening phase before total knee replacement (TKR) surgery, 10 to14 day postoperative dosing phase, and 4-week follow-up phase. The hypothesis of this study is JNJ-70033093 reduces risk of total VTE during treatment period. The total duration of participation following randomization will be approximately 6 weeks. Efficacy evaluations include unilateral venography assessment of operated leg and assessments of symptomatic DVT, PE, or death. Safety evaluation includes adverse events, clinical laboratory tests, and physical examinations. The safety and efficacy will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Medically stable and appropriate for anticoagulant prophylaxis as determined by the investigator on the basis of physical examination, medical history, and vital signs performed as part of screening for elective total knee replacement (TKR) surgery
* Medically stable and appropriate for anticoagulant prophylaxis on the basis of clinical laboratory tests performed as part of local standard-of-care as part of screening for elective TKR surgery
* Has plans to undergo an elective primary unilateral TKR surgery
* A woman must be- a) Not of childbearing potential; b) Of childbearing potential and practicing a highly effective method of contraception (failure rate of less than \[\<\]1 percent \[%\] per year when used consistently and correctly) and agrees to remain on a highly effective method for the duration of study drug with JNJ-70033093 plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle) for a total of 34 days after the completion of treatment, pregnancy testing (serum or urine) prior to the first dose of study drug
* Willing and able to adhere to the lifestyle restrictions specified in this protocol

Exclusion Criteria:

* History of any condition for which the use of low molecular-weight heparin (LMWH) is not recommended in the opinion of the investigator (for example, previous allergic reaction, creatinine clearance \<30 milliliter per minute \[mL/minute\])
* History of severe hepatic impairment
* Planned bilateral revision or unicompartmental procedure
* Unable to undergo venography (for example, due to contrast agent allergy, poor venous access, or impaired renal function that would increase the risk of contrast-induced nephropathy
* Known previous pulmonary embolism (PE) or deep vein thrombosis (DVT) in either lower extremity

Primary outcomes:
measure: Number of Participants With Total Venous Thromboembolism (VTE) (CEC-adjudicated)
timeFrame: Up to Day 14
Secondary outcomes:
measure: Number of Participants With Any Bleeding Event (CEC-adjudicated)
timeFrame: Up to Day 14; Up to Day 52
measure: Number of Participants With Total VTE (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Number of Participants With Composite of Major and Clinically Relevant Nonmajor Bleeding (CRNM) Events (CEC-adjudicated)
timeFrame: Up to Day 14, Up to Day 52
measure: Number of Participants With Major Bleeding Events (CEC-adjudicated)
timeFrame: Up to Day 14; Up to Day 52
measure: Number of Participants With CRNM Bleeding Events (CEC-adjudicated)
timeFrame: Up to Day 14; Up to Day 52
measure: Number of Participants With Minimal Bleeding Events (CEC-adjudicated)
timeFrame: Up to Day 14; Up to Day 52
measure: Number of Participants With Major or CRNM Bleeding Events (CEC-adjudicated)
timeFrame: Up to Day 14; Up to Day 52
measure: Number of Participants With Major VTE (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Number of Participants With Major VTE (CEC-adjudicated)
timeFrame: Up to Day 14
measure: Number of Participants With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)
timeFrame: Up to Day 14
measure: Number of Participants With Proximal DVT (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Number of Participants With Distal DVT (CEC-adjudicated)
timeFrame: Up to Day 14
measure: Number of Participants With Distal DVT (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
timeFrame: Up to Day 14
measure: Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Number of Participants With Deaths (CEC-adjudicated)
timeFrame: Up to Day 14
measure: Number of Participants With Deaths (CEC-adjudicated)
timeFrame: Up to Day 52
measure: Apparent Clearance (CL/F) of JNJ-70033093
timeFrame: Up to Day 14
measure: Apparent Volume of Distribution (V/F) of JNJ-70033093
timeFrame: Up to Day 14
measure: Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex
timeFrame: Up to Day 14
measure: Impact of Selected Demographic: Age on CL/F
timeFrame: Up to Day 14
measure: Impact of Selected Demographic: Weight on CL/F
timeFrame: Up to Day 14
measure: Impact of Selected Laboratory Values: Renal Function on CL/F
timeFrame: Up to Day 14
measure: Impact of Selected Demographics: Sex on Apparent Volume of Distribution (V/F)
timeFrame: Up to Day 14
measure: Impact of Selected Demographics : Age on V/F
timeFrame: Up to Day 14
measure: Impact of Selected Demographics : Weight on V/F
timeFrame: Up to Day 14
measure: Impact of Selected Laboratory Values: Renal Function on V/F
timeFrame: Up to Day 14
measure: Trend Test for Primary Efficacy Event Rate (CEC Adjudicated) by Multiple Comparison Procedure - Modelling (MCP-Mod) Approach
timeFrame: Up to 14 days
measure: Trend Test for the Composite of On-Treatment Major and Clinically Relevant Nonmajor Bleeding (CEC Adjudicated) by MCP-Mod Approach
timeFrame: Up to 14 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Research Associates, Inc.
state: Alabama
city: Phoenix
country: United States
facility: Arizona Research Center
state: Arizona
city: Little Rock
country: United States
facility: Bowen Hefley Orthopedics
state: Arkansas
city: Torrance
country: United States
facility: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
state: California
city: Englewood
country: United States
facility: Denver Metro Orthopedics, PC
state: Colorado
city: Pinellas Park
country: United States
facility: DMI Research
state: Florida
city: Sarasota
country: United States
facility: Gulfcoast Research Institute
state: Florida
city: Tamarac
country: United States
facility: University Orthopedic and Joint Replacement Center
state: Florida
city: Houston
country: United States
facility: Memorial Hermann Memorial City Medical Center
state: Texas
city: Caba
country: Argentina
facility: Clinica Adventista Belgrano
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Britanico de Buenos Aires
city: Córdoba
country: Argentina
facility: Hospital San Roque
city: Córdoba
country: Argentina
facility: Clínica Chutro
city: La Plata
country: Argentina
facility: Hospital Italiano La Plata
city: Rosario
country: Argentina
facility: Instituto de Investigaciones Clinicas Rosario
city: San Martín
country: Argentina
facility: Sanatorio Corporación Médica de General San Martín
city: Antwerpen
country: Belgium
facility: ZNA Middelheim
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis
city: Merksem
country: Belgium
facility: ZNA Jan Palfijn
city: Belo Horizonte
country: Brazil
facility: Hospital Sao Francisco de Assis
city: Santo Andre
country: Brazil
facility: Hospital e Maternidade Dr Christovao da Gama S.A
city: Santo André
country: Brazil
facility: Hospital Estadual Mario covas
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski
city: Sofa
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital Sofiamed Sofia
city: Sofia
country: Bulgaria
facility: MHAT Tzaritza Joanna
city: Stara Zagora
country: Bulgaria
facility: Medical Center - Medical Complex BEROE EOOD
city: Ajax
country: Canada
facility: Lakeridge Health
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Corporation
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Research Institute
state: Ontario
city: Windsor
country: Canada
facility: Medical Investigative and Clinical Evaluation Inc
state: Ontario
city: Kifisia
country: Greece
facility: General Hospital of Attiki 'KAT'
city: Nea Ionia
country: Greece
facility: General Hospital of Nea Ionia 'Konstantopoulio'
city: Patras
country: Greece
facility: University General Hospital of Rio Patras
city: Thessaloniki
country: Greece
facility: Papageorgiou General Hospital
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem
city: Gyõr
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Kaposvar
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz
city: Kecskemét
country: Hungary
facility: Bacs-kiskun Megyei Korhaz
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem
city: Szekesfehervar
country: Hungary
facility: Fejer Varmegyei Szent Gyorgy Egyetemi Oktatokorhaz
city: Szolnok
country: Hungary
facility: MAV Korhaz es Rendelointezet
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Bergamo
country: Italy
facility: Cliniche Humanitas Gavazzeni
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Istituto Ortopedico Rizzoli
city: Pavia
country: Italy
facility: Policlinico S. Matteo
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza
city: Chiba
country: Japan
facility: Matsudo City General Hospital
city: Hakodate
country: Japan
facility: Hakodate Goryoukaku Hospital
city: Hamamatsu
country: Japan
facility: Japanese Red Cross Hamamatsu Hospital
city: Itami-shi
country: Japan
facility: Itami City Hospital
city: Kagoshima-shi
country: Japan
facility: Yonemori Hospital
city: Kitakyushu-shi
country: Japan
facility: Japan Community Health care Organization Kyushu Hospital
city: Matsumoto
country: Japan
facility: Marunouchi Hospital
city: Nagoya
country: Japan
facility: Chubu Rosai Hospital
city: Nerima-Ku
country: Japan
facility: Juntendo University Nerima Hospital
city: Okayama
country: Japan
facility: National Hospital Organization Okayama Medical Center
city: Okinawa
country: Japan
facility: Yuuai Medical Center
city: Saitama-shi
country: Japan
facility: Saitama City Hospital
city: Saitama
country: Japan
facility: Japan Community Health Care Organization Saitama Medical Center
city: Suzaka
country: Japan
facility: Nagano Prefectural Shinshu Medical Center
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Bielsk Podlaski
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej w Bielsku Podlaskim Oddzial Urazowo Ortopedyczny
city: Grajewo
country: Poland
facility: Szpital Ogolny im. W. Ginela, Oddzial Urazowo-Ortopedyczny
city: Kielce
country: Poland
facility: Wojewodzki Szpital Zespolony w Kielcach, Klinika Chirurgii Ortopedyczno-Urazowej
city: Krakow
country: Poland
facility: Oddzial Ortopedii i Traumatologii Narzadu Ruchu Szpital Specjalistyczny im Ludwika Rydygiera
city: Lodz
country: Poland
facility: CSK UM Klinika Ortopedii
city: Lublin
country: Poland
facility: Oddzial Urazowo-Ortopedyczny Wojewodzki Szpital Specjalistyczny
city: Tarnow
country: Poland
facility: Oddzial Ortopedii Specjalistyczny Szpital im. E.Szczeklika
city: Warszawa
country: Poland
facility: Oddzial Chirurgii Urazowej iOrtopedycznej Wojewodzki Szpital Brodnowski SPZOZ
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im Jana Mikulicza Radeckiego we Wroclawiu
city: Aveiro
country: Portugal
facility: Centro Hospitalar do Baixo Vouga - Hospital Infante Dom Pedro
city: Cascais
country: Portugal
facility: Hosp de Cascais
city: Porto
country: Portugal
facility: H. Santo António - Centro Hospitalar do Porto
city: Setubal
country: Portugal
facility: CHS - Hosp. Orto. Sant'Iago do Outao
city: Viana do Castelo
country: Portugal
facility: ULSAM, EPE - Hospital de Santa Luzia
city: Kurgan
country: Russian Federation
facility: National Medical Research Center of Traumatology and Orthopaedics n.a. G.A. Ilizarov
city: Moscow
country: Russian Federation
facility: Private Healthcare Institution 'Clinical Hospital 'RZD-Medcine' n.a. N.A.Semashko'
city: Nizhniy Novgorod
country: Russian Federation
facility: Privolzhsky Regional Medical Center of Federal Medical and Biological Agency
city: Saint-Petersburg
country: Russian Federation
facility: National medical research center of Traumatology and Orthopaedics n.a. R.R.Vreden
city: Samara
country: Russian Federation
facility: State Healthcare Institution Samara Regional Clinical Hospital named after V.D.Seredavin
city: Smolensk
country: Russian Federation
facility: Smolensk Federal Center of Traumatology, Orthopedics and Endoprothesis Replacement
city: Sochi
country: Russian Federation
facility: Sochi City Hospital #4
city: Pretoria
country: South Africa
facility: Steve Biko Academic Hospital
city: Worcester
country: South Africa
facility: Clinical Project Research SA
city: Alcorcón
country: Spain
facility: Hosp. Univ. Fundacion Alcorcon
city: Badalona
country: Spain
facility: Hosp. Univ. Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hosp. Univ. de Bellvitge
city: Barcelona
country: Spain
facility: Hosp Univ Vall D Hebron
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: Madrid
country: Spain
facility: Hosp. Univ. 12 de Octubre
city: Madrid
country: Spain
facility: Hosp. Univ. La Paz
city: Sabadell
country: Spain
facility: Corporacio Sanitari Parc Tauli
city: Valencia
country: Spain
facility: Hosp. Clinico Univ. de Valencia
city: Valencia
country: Spain
facility: Hosp. Univ. I Politecni La Fe
city: Adana
country: Turkey
facility: Adana City Hospital
city: Ankara
country: Turkey
facility: Diskapi Yildırim Beyazid Training and Research Hospital
city: Ankara
country: Turkey
facility: Yıldırım Beyazıt University Yenimahalle Training and Research Hospital
city: Antalya
country: Turkey
facility: Antalya Training And Research Hospital
city: Istanbul
country: Turkey
facility: Bakirkoy Training and Research Hospital
city: Istanbul
country: Turkey
facility: Sisli Etfal Research Training Hospital
city: Izmir
country: Turkey
facility: Izmir Tepecik Training and Research Hospital
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk Regional Clinical Hospital
city: Kharkiv
country: Ukraine
facility: Institute of Spine and JointPathology named after Prof.Sytenko of NationalAcademy of MedicalSciences
city: Kharkiv
country: Ukraine
facility: Municipal Institution of Health Care 'Kharkiv Regional Clinical Traumatology Hospital'
city: Kyiv
country: Ukraine
facility: Kyiv Regional Clinical Hospital
city: Lviv-Vynnyky
country: Ukraine
facility: Communal Institution of Lviv Regional Council 'Lypa Lviv Regional Hospital'
city: Odesa
country: Ukraine
facility: Municipal Non-profit Enterprise 'Odesa Regional Clinical Hospital' Odesa Regional Council
city: Vinnytsia
country: Ukraine
facility: Vinnytsya Regional Clinical Hospital named after M.I.Pirogov
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, Mahaffey KW, Notani RS, Roberts R, Segers A, Raskob GE; AXIOMATIC-TKR Investigators. Milvexian for the Prevention of Venous Thromboembolism. N Engl J Med. 2021 Dec 2;385(23):2161-2172. doi: 10.1056/NEJMoa2113194. Epub 2021 Nov 15.