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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
1,242
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.
Participants will receive JNJ-70033093 50 mg (2\*25 mg capsules) BID orally for 10 to 14 postoperative days.
Participants will receive JNJ-70033093 100 mg (1\*100 mg capsule) BID, orally for 10 to 14 postoperative days.
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.
Time frame: Up to Day 14
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.
Time frame: Up to Day 14; Up to Day 52
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.
Time frame: Up to Day 52
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.
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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.
Participants will receive placebo matching to JNJ-70033093, orally.
Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.
Central Research Associates, Inc.
Birmingham, Alabama, United States
Arizona Research Center
Phoenix, Arizona, United States
Bowen Hefley Orthopedics
Little Rock, Arkansas, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Torrance, California, United States
Denver Metro Orthopedics, PC
Englewood, Colorado, 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
Memorial Hermann Memorial City Medical Center
Houston, Texas, United States
Hospital Britanico de Buenos Aires
Buenos Aires, Argentina
...and 107 more locations
Time frame: Up to Day 14, Up to Day 52
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.
Time frame: Up to Day 14; Up to Day 52
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.
Time frame: Up to Day 14; Up to Day 52
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.
Time frame: Up to Day 14; Up to Day 52
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.
Time frame: Up to Day 14; Up to Day 52
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.
Time frame: Up to Day 52
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.
Time frame: Up to Day 14
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.
Time frame: Up to Day 14
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.
Time frame: Up to Day 52
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.
Time frame: Up to Day 14
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.
Time frame: Up to Day 52
Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
Number of participants with nonfatal PE (adjudicated by CEC) were reported.
Time frame: Up to Day 14
Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
Number of participants with nonfatal PE (adjudicated by CEC) were reported.
Time frame: Up to Day 52
Number of Participants With Deaths (CEC-adjudicated)
Number of participants with deaths (CEC-adjudicated) were reported.
Time frame: Up to Day 14
Number of Participants With Deaths (CEC-adjudicated)
Number of participants with deaths (CEC-adjudicated) were reported.
Time frame: Up to Day 52
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.
Time frame: Up to Day 14
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.
Time frame: Up to Day 14
Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex
Impact of demographic character (sex) on CL/F was assessed.
Time frame: Up to Day 14
Impact of Selected Demographic: Age on CL/F
Impact of age on CL/F was assessed.
Time frame: Up to Day 14
Impact of Selected Demographic: Weight on CL/F
Impact of weight on CL/F was assessed.
Time frame: Up to Day 14
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.
Time frame: Up to Day 14
Impact of Selected Demographics: Sex on Apparent Volume of Distribution (V/F)
Impact of sex on V/F was assessed.
Time frame: Up to Day 14
Impact of Selected Demographics : Age on V/F
Impact of age on V/F was assessed.
Time frame: Up to Day 14
Impact of Selected Demographics : Weight on V/F
Impact of weight on V/F was assessed.
Time frame: Up to Day 14
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.
Time frame: Up to Day 14
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.
Time frame: Up to 14 days
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.
Time frame: Up to 14 days