A Study of JNJ-70033093 (BMS-986177) Versus Subcutaneous Enoxaparin in Participants Undergoing Elective Total Knee Replacement Surgery

Arthroplasty, Replacement, Knee Clinical Trial

— AXIOMATIC-TKR  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03891524
• Other study ID #: CR108600
• Secondary ID: 70033093THR20012
• Status: Completed
• Phase: Phase 2
• Start date: June 17, 2019
• Est. completion date: April 6, 2021

Study information

• Verified date: July 2022
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1242
• Est. completion date: April 6, 2021
• Est. primary completion date: April 6, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Arthroplasty, Replacement, Knee

Intervention

Drug:
• JNJ-70033093 25 mg
Participants will receive JNJ-70033093 25 mg (1*25 mg capsule) BID (in Group A) or once daily (in Group E), orally for 10 to 14 postoperative days.
• JNJ-70033093 50 mg
Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.
• JNJ-70033093 100 mg
Participants will receive JNJ-70033093 100 mg (1*100 mg capsule) BID, orally for 10 to 14 postoperative days.
• JNJ-70033093 200 mg
Participants will receive JNJ-70033093 200 mg (2*100 mg capsules) BID (in Group D) or once daily (in Group F), orally for 10 to 14 postoperative days.
• Placebo
Participants will receive placebo matching to JNJ-70033093, orally.
• Enoxaparin 40 mg
Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Locations

Country	Name	City	State
Argentina	Clínica Adventista Belgrano	Caba
Argentina	Hospital Britanico de Buenos Aires	Ciudad Autonoma de Buenos Aires
Argentina	Clínica Chutro	Córdoba
Argentina	Hospital San Roque	Córdoba
Argentina	Hospital Italiano La Plata	La Plata
Argentina	Instituto de Investigaciones Clinicas Rosario	Rosario
Argentina	Sanatorio Corporación Médica de General San Martín	San Martín
Belgium	ZNA Middelheim	Antwerpen
Belgium	Ziekenhuis Oost-Limburg	Genk
Belgium	Jessa Ziekenhuis	Hasselt
Belgium	ZNA Jan Palfijn	Merksem
Brazil	Hospital Sao Francisco de Assis	Belo Horizonte
Brazil	Hospital e Maternidade Dr Christovão da Gama	Santo André
Brazil	Hospital Estadual Mario covas	Santo André
Bulgaria	University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski	Pleven
Bulgaria	Acibadem City Clinic Tokuda Hospital	Sofa
Bulgaria	MHAT Tzaritza Joanna	Sofia
Bulgaria	University Multiprofile Hospital Sofiamed Sofia	Sofia
Bulgaria	Medical Center - Medical Complex BEROE EOOD	Stara Zagora
Canada	Lakeridge Health	Ajax	Ontario
Canada	Hamilton Health Sciences Corporation	Hamilton	Ontario
Canada	The Ottawa Hospital Research Institute	Ottawa	Ontario
Canada	Medical Investigative and Clinical Evaluation Inc	Windsor	Ontario
Greece	General Hospital of Attiki 'KAT'	Kifisia
Greece	General Hospital of Nea Ionia 'Konstantopoulio'	Nea Ionia
Greece	University General Hospital of Rio Patras	Patra
Greece	Papageorgiou General Hospital	Thessaloniki
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz	Gyõr
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz	Kaposvar
Hungary	Bacs-kiskun Megyei Korhaz	Kecskemét
Hungary	Szegedi Tudomanyegyetem	Szeged
Hungary	Fejer Megyei Szent Gyorgy Egyetemi Oktatokorhaz	Szekesfehervar
Hungary	MAV Korhaz es Rendelointezet	Szolnok
Israel	Carmel Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Meir Medical Center	Kfar Saba
Israel	Kaplan Medical Center	Rehovot
Italy	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	Cliniche Humanitas Gavazzeni	Bergamo
Italy	Istituto Ortopedico Rizzoli	Bologna
Italy	Policlinico S. Matteo	Pavia
Italy	Istituto Clinico Humanitas	Rozzano
Italy	A.O.U. Città della Salute e della Scienza	Torino
Japan	Matsudo City General Hospital	Chiba
Japan	Hakodate Goryokaku Hospital	Hakodate
Japan	Japanese Red Cross Hamamatsu Hospital	Hamamatsu
Japan	Itami City Hospital	Itami-shi
Japan	Yonemori Hospital	Kagoshima-shi
Japan	Japan Community Health care Organization Kyushu Hospital	Kitakyushu-shi,
Japan	Marunouchi Hospital	Matsumoto
Japan	Chubu Rosai Hospital	Nagoya
Japan	Juntendo University Nerima Hospital	Nerima-Ku
Japan	National Hospital Organization Okayama Medical Center	Okayama
Japan	Yuuai Medical Center	Okinawa, Tomigusuku-shi
Japan	Japan Community Health Care Organization Saitama Medical Center	Saitama
Japan	Saitama City Hospital	Saitama-shi
Japan	Nagano Prefectural Shinshu Medical Center	Suzaka
Japan	Juntendo University Hospital	Tokyo
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej w Bielsku Podlaskim,Oddzial Urazowo-Ortopedyczny	Bielsk Podlaski
Poland	Szpital Ogolny im. W. Ginela, Oddzial Urazowo-Ortopedyczny	Grajewo
Poland	Wojewodzki Szpital Zespolony w Kielcach, Klinika Chirurgii Ortopedyczno-Urazowej	Kielce
Poland	Oddzial Ortopedii i Traumatologii Narzadu Ruchu Szpital Specjalistyczny im. Ludwika Rydygiera	Krakow
Poland	CSK UM Klinika Ortopedii	Lodz
Poland	Oddzial Urazowo-Ortopedyczny Wojewodzki Szpital Specjalistyczny	Lublin
Poland	Oddzial Ortopedii Specjalistyczny Szpital im. E.Szczeklika	Tarnow
Poland	Oddzial Chirurgii Urazowej iOrtopedycznej,Wojewodzki Szpital Brodnowski, SPZOZ	Warszawa
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Portugal	Centro Hospitalar do Baixo Vouga - Hospital Infante Dom Pedro	Aveiro
Portugal	Hosp. de Cascais	Cascais
Portugal	H. Santo António - Centro Hospitalar do Porto	Porto
Portugal	CHS - Hosp. Orto. Sant'Iago do Outao	Setubal
Portugal	ULSAM, EPE - Hospital de Santa Luzia	Viana do Castelo
Russian Federation	National Medical Research Center of Traumatology and Orthopaedics n.a. G.A. Ilizarov	Kurgan
Russian Federation	Private Healthcare Institution 'Clinical Hospital 'RZD-Medcine' n.a. N.A.Semashko'	Moscow
Russian Federation	Privolzhsky Regional Medical Center of Federal Medical and Biological Agency	Nizhniy Novgorod
Russian Federation	National medical research center of Traumatology and Orthopaedics n.a. R.R.Vreden	Saint-Petersburg
Russian Federation	State Healthcare Institution Samara Regional Clinical Hospital named after V.D.Seredavin	Samara
Russian Federation	Smolensk Federal Center of Traumatology, Orthopedics and Endoprothesis Replacement	Smolensk
Russian Federation	Sochi City Hospital #4	Sochi
South Africa	Steve Biko Academic Hospital	Pretoria
South Africa	Clinical Project Research SA	Worcester
Spain	Hosp. Univ. Fundacion Alcorcon	Alcorcón
Spain	Hosp. Univ. Germans Trias I Pujol	Badalona
Spain	Hosp. Clinic I Provincial de Barcelona	Barcelona
Spain	Hosp. Univ. de Bellvitge	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. La Paz	Madrid
Spain	Corporacio Sanitari Parc Tauli	Sabadell
Spain	Hosp. Clinico Univ. de Valencia	Valencia
Spain	Hosp. Univ. I Politecni La Fe	Valencia
Turkey	Adana City Hospital	Adana
Turkey	Diskapi Yildirim Beyazid Training and Research Hospital	Ankara
Turkey	Yildirim Beyazit University Yenimahalle Training and Research Hospital	Ankara
Turkey	Antalya Training And Research Hospital	Antalya
Turkey	Bakirkoy Training and Research Hospital	Istanbul
Turkey	Sisli Etfal Research Training Hospital	Istanbul
Turkey	Izmir Tepecik Training and Research Hospital	Izmir
Ukraine	Ivano-Frankivsk Regional Clinical Hospital	Ivano-Frankivsk
Ukraine	Institute of Spine and JointPathology named after Prof.Sytenko of NationalAcademy of MedicalSciences	Kharkiv
Ukraine	Municipal Institution of Health Care 'Kharkiv Regional Clinical Traumatology Hospital'	Kharkiv
Ukraine	Kyiv Regional Clinical Hospital	Kyiv
Ukraine	Communal Institution of Lviv Regional Council 'Lypa Lviv Regional Hospital'	Lviv-Vynnyky
Ukraine	Municipal Non-profit Enterprise 'Odesa Regional Clinical Hospital' Odesa Regional Council	Odesa
Ukraine	Vinnytsya Regional Clinical Hospital named after M.I.Pirogov	Vinnytsia
United States	Central Research Associates, Inc.	Birmingham	Alabama
United States	Denver Metro Orthopedics, PC	Englewood	Colorado
United States	Memorial Hermann Memorial City Medical Center	Houston	Texas
United States	Bowen Hefley Orthopedics	Little Rock	Arkansas
United States	Arizona Research Center	Phoenix	Arizona
United States	DMI Research	Pinellas Park	Florida
United States	Gulfcoast Research Institute	Sarasota	Florida
United States	University Orthopedic and Joint Replacement Center	Tamarac	Florida
United States	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Bulgaria,  Canada,  Greece,  Hungary,  Israel,  Italy,  Japan,  Poland,  Portugal,  Russian Federation,  South Africa,  Spain,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Total Venous Thromboembolism (VTE) (CEC-adjudicated)	Total VTE was defined as the composite of clinical events committee (CEC)-adjudicated proximal and/or distal Deep Vein Thrombosis (DVT) (asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic), nonfatal pulmonary embolism (PE), or any death.	Up to Day 14
Secondary	Number of Participants With Any Bleeding Event (CEC-adjudicated)	Any bleeding was defined as the composite of major bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria modified for the surgical setting, clinically relevant nonmajor bleeding events, or minimal bleeding events as assessed by the CEC.	Up to Day 14; Up to Day 52
Secondary	Number of Participants With Total VTE (CEC-adjudicated)	Total VTE was defined as the composite of (CEC-adjudicated) proximal and/or DVT (asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic), nonfatal PE, or any death.	Up to Day 52
Secondary	Number of Participants With Composite of Major and Clinically Relevant Nonmajor Bleeding (CRNM) Events (CEC-adjudicated)	Composite of Major bleeding event (BE): Fatal bleeding; bleeding that is symptomatic and occurs in critical area/organ and/or; extrasurgical site bleeding causing fall in Hemoglobin (Hb) level of 20 grams per liter (g/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; surgical site bleeding that requires second intervention open, arthroscopic, endovascular,or hemarthrosis resulting in prolonged hospitalization, deep wound infection and/or either unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE is still considered clinically relevant for example: Epistaxis, Gastrointestinal bleed,Hematuria,Bruising/ecchymosis,Hemoptysis,Hematoma.	Up to Day 14, Up to Day 52
Secondary	Number of Participants With Major Bleeding Events (CEC-adjudicated)	Number of participants with major BE (adjudicated by CEC) were reported. Major Bleeding events were defined as: fatal bleeding; bleeding that is symptomatic and occurs in critical area/organ and/or; extrasurgical site bleeding causing fall in Hb level of 20 g/L or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; requires second intervention open, arthroscopic, endovascular, or hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; either unexpected and prolonged and/or sufficiently large to cause hemodynamic instability.	Up to Day 14; Up to Day 52
Secondary	Number of Participants With CRNM Bleeding Events (CEC-adjudicated)	Number of participants with CRNM bleeding events (adjudicated by CEC) were reported. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE is still considered clinically relevant for example: epistaxis, gastrointestinal bleed, hematuria, bruising/ecchymosis, hemoptysis, hematoma.	Up to Day 14; Up to Day 52
Secondary	Number of Participants With Minimal Bleeding Events (CEC-adjudicated)	Number of participants with minimal bleeding events (adjudicated by CEC) were reported. Minimal bleeding event was defined as any bleeding event not met major or CRNM criteria. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE is still considered clinically relevant for example: epistaxis, gastrointestinal bleed, hematuria, bruising/ecchymosis, hemoptysis, hematoma.	Up to Day 14; Up to Day 52
Secondary	Number of Participants With Major or CRNM Bleeding Events (CEC-adjudicated)	Major Bleeding events were defined as: fatal bleeding; bleeding that is symptomatic and occurs in critical area/organ and/or; extrasurgical site bleeding causing fall in Hb level of 20 g/L or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; requires second intervention open, arthroscopic, endovascular, or hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; either unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE is still considered clinically relevant for example: epistaxis, gastrointestinal bleed, hematuria, bruising/ecchymosis, hemoptysis, hematoma.	Up to Day 14; Up to Day 52
Secondary	Number of Participants With Major VTE (CEC-adjudicated)	Number of participants with major VTE (adjudicated by CEC) were reported. Major VTE was defined as a composite of proximal DVT (asymptomatic confirmed by venography or objectively confirmed symptomatic), nonfatal PE, or any death.	Up to Day 52
Secondary	Number of Participants With Major VTE (CEC-adjudicated)	Number of participants with major VTE (adjudicated by CEC) were reported. Major VTE was defined as a composite of proximal DVT (asymptomatic confirmed by venography or objectively confirmed symptomatic), nonfatal PE, or any death.	Up to Day 14
Secondary	Number of Participants With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)	Number of participants with proximal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.	Up to Day 14
Secondary	Number of Participants With Proximal DVT (CEC-adjudicated)	Number of participants with proximal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.	Up to Day 52
Secondary	Number of Participants With Distal DVT (CEC-adjudicated)	Number of participants with distal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.	Up to Day 14
Secondary	Number of Participants With Distal DVT (CEC-adjudicated)	Number of participants with distal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.	Up to Day 52
Secondary	Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)	Number of participants with nonfatal PE (adjudicated by CEC) were reported.	Up to Day 14
Secondary	Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)	Number of participants with nonfatal PE (adjudicated by CEC) were reported.	Up to Day 52
Secondary	Number of Participants With Deaths (CEC-adjudicated)	Number of participants with deaths (CEC-adjudicated) were reported.	Up to Day 14
Secondary	Number of Participants With Deaths (CEC-adjudicated)	Number of participants with deaths (CEC-adjudicated) were reported.	Up to Day 52
Secondary	Apparent Clearance (CL/F) of JNJ-70033093	Apparent clearance of a drug was defined as a measure of the rate at which a drug got metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Up to Day 14
Secondary	Apparent Volume of Distribution (V/F) of JNJ-70033093	V/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug.	Up to Day 14
Secondary	Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex	Impact of demographic character (sex) on CL/F was assessed.	Up to Day 14
Secondary	Impact of Selected Demographic: Age on CL/F	Impact of age on CL/F was assessed.	Up to Day 14
Secondary	Impact of Selected Demographic: Weight on CL/F	Impact of weight on CL/F was assessed.	Up to Day 14
Secondary	Impact of Selected Laboratory Values: Renal Function on CL/F	Impact of renal function on CL/F was assessed. The outcome measure was reported based on CRCL.	Up to Day 14
Secondary	Impact of Selected Demographics: Sex on Apparent Volume of Distribution (V/F)	Impact of sex on V/F was assessed.	Up to Day 14
Secondary	Impact of Selected Demographics : Age on V/F	Impact of age on V/F was assessed.	Up to Day 14
Secondary	Impact of Selected Demographics : Weight on V/F	Impact of weight on V/F was assessed.	Up to Day 14
Secondary	Impact of Selected Laboratory Values: Renal Function on V/F	Impact of renal function on V/F was assessed. The outcome measure is reported based on CRCL.	Up to Day 14
Secondary	Trend Test for Primary Efficacy Event Rate (CEC Adjudicated) by Multiple Comparison Procedure - Modelling (MCP-Mod) Approach	The dose-response trend test based on the MCP-Mod framework consisted of contrast tests defined by prespecified candidate models (4 Emax dose-response models with varying degrees of ED50). Each model was evaluated for significance of trend, based on its optimal contrast, resulting in four t-test statistics, one for each candidate model. The t-test statistics were adjusted for the fact that 4 candidate models were included in the trend testing. The dose response of the drug was then established if the maximum of the t-test statistics exceeded the 95th percentile critical value. Here 'number' signifies the estimated response rate.	Up to 14 days
Secondary	Trend Test for the Composite of On-Treatment Major and Clinically Relevant Nonmajor Bleeding (CEC Adjudicated) by MCP-Mod Approach	The dose-response trend test based on the MCP-Mod framework consisted of contrast tests defined by prespecified candidate models (4 Emax dose-response models with varying degrees of ED50). Each model was evaluated for significance of trend, based on its optimal contrast, resulting in four t-test statistics, one for each candidate model. The t-test statistics were adjusted for the fact that 4 candidate models were included in the trend testing. The dose response of the drug was then established if the maximum of the t-test statistics exceeded the 95th percentile critical value. Here 'number' signifies the estimated response rate.	Up to 14 days