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

Study Overview
=================
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.

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

Conditions
-----------------
Arthroplasty, Replacement, Knee

Intervention / Treatment
-----------------
* Drug: JNJ-70033093 25 mg
* Drug: JNJ-70033093 50 mg
* Drug: JNJ-70033093 100 mg
* Drug: JNJ-70033093 200 mg
* Drug: Placebo
* Drug: Enoxaparin 40 mg


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: JNJ-70033093 25 mg + Placebo BID<br>Participants will receive JNJ-70033093 25 milligram (mg) (1*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 25 mg<br>* 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.<br>* Other names: BMS-986177;Drug: Placebo<br>* Participants will receive placebo matching to JNJ-70033093, orally.<br>|
| Experimental: Group B: JNJ-70033093 50 mg BID<br>Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 50 mg<br>* Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.<br>* Other names: BMS-986177;|
| Experimental: Group C: JNJ-70033093 100 mg + Placebo BID<br>Participants will receive JNJ-70033093 100 mg (1*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 100 mg<br>* Participants will receive JNJ-70033093 100 mg (1*100 mg capsule) BID, orally for 10 to 14 postoperative days.<br>* Other names: BMS-986177;Drug: Placebo<br>* Participants will receive placebo matching to JNJ-70033093, orally.<br>|
| Experimental: Group D: JNJ-70033093 200 mg BID<br>Participants will receive JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 200 mg<br>* 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.<br>* Other names: BMS-986177;|
| Experimental: Group E: JNJ-70033093 25 mg Once Daily + Placebo<br>Participants will receive JNJ-70033093 25 mg (1*25 mg capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 25 mg<br>* 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.<br>* Other names: BMS-986177;Drug: Placebo<br>* Participants will receive placebo matching to JNJ-70033093, orally.<br>|
| Experimental: Group F: JNJ-70033093 200 mg Once Daily + Placebo<br>Participants will receive JNJ-70033093 200 mg (2*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 200 mg<br>* 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.<br>* Other names: BMS-986177;Drug: Placebo<br>* Participants will receive placebo matching to JNJ-70033093, orally.<br>|
| Experimental: Group G: JNJ-70033093 50 mg once daily + Placebo<br>Participants will receive JNJ-70033093 50 mg (2*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days. | Drug: JNJ-70033093 50 mg<br>* Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.<br>* Other names: BMS-986177;Drug: Placebo<br>* Participants will receive placebo matching to JNJ-70033093, orally.<br>|
| Active Comparator: Group I: Enoxaparin 40 mg Once Daily<br>Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days. | Drug: Enoxaparin 40 mg<br>* Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Number of Participants With Deaths (CEC-adjudicated) | Number of participants with deaths (CEC-adjudicated) were reported. | Up to Day 14 | 
| Number of Participants With Deaths (CEC-adjudicated) | Number of participants with deaths (CEC-adjudicated) were reported. | 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. | 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. | 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. | Up to Day 14 | 
| Impact of Selected Demographic: Age on CL/F | Impact of age on CL/F was assessed. | Up to Day 14 | 
| Impact of Selected Demographic: Weight on CL/F | Impact of weight on CL/F was assessed. | 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. | Up to Day 14 | 
| Impact of Selected Demographics: Sex on Apparent Volume of Distribution (V/F) | Impact of sex on V/F was assessed. | Up to Day 14 | 
| Impact of Selected Demographics : Age on V/F | Impact of age on V/F was assessed. | Up to Day 14 | 
| Impact of Selected Demographics : Weight on V/F | Impact of weight on V/F was assessed. | 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. | 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. | 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. | Up to 14 days |