We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03891524
Recruitment Status : Completed
First Posted : March 27, 2019
Results First Posted : July 15, 2022
Last Update Posted : July 15, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Janssen Research & Development, LLC

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.

Condition or disease Intervention/treatment Phase
Arthroplasty, Replacement, Knee 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 Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1242 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: Treatment arms and study drug dose regimens will be blinded.
Primary Purpose: Prevention
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
Actual Study Start Date : June 17, 2019
Actual Primary Completion Date : April 6, 2021
Actual Study Completion Date : April 6, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Knee Replacement

Arm Intervention/treatment
Experimental: Group A: JNJ-70033093 25 mg + Placebo BID
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
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.
Other Name: BMS-986177

Drug: Placebo
Participants will receive placebo matching to JNJ-70033093, orally.

Experimental: Group B: JNJ-70033093 50 mg BID
Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.
Drug: JNJ-70033093 50 mg
Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.
Other Name: BMS-986177

Experimental: Group C: JNJ-70033093 100 mg + Placebo BID
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
Participants will receive JNJ-70033093 100 mg (1*100 mg capsule) BID, orally for 10 to 14 postoperative days.
Other Name: BMS-986177

Drug: Placebo
Participants will receive placebo matching to JNJ-70033093, orally.

Experimental: Group D: JNJ-70033093 200 mg BID
Participants will receive JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days.
Drug: 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.
Other Name: BMS-986177

Experimental: Group E: JNJ-70033093 25 mg Once Daily + Placebo
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
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.
Other Name: BMS-986177

Drug: Placebo
Participants will receive placebo matching to JNJ-70033093, orally.

Experimental: Group F: JNJ-70033093 200 mg Once Daily + Placebo
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
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.
Other Name: BMS-986177

Drug: Placebo
Participants will receive placebo matching to JNJ-70033093, orally.

Experimental: Group G: JNJ-70033093 50 mg once daily + Placebo
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
Participants will receive JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.
Other Name: BMS-986177

Drug: Placebo
Participants will receive placebo matching to JNJ-70033093, orally.

Active Comparator: Group I: Enoxaparin 40 mg Once Daily
Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.
Drug: Enoxaparin 40 mg
Participants will receive enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.




Primary Outcome Measures :
  1. Number of Participants With Total Venous Thromboembolism (VTE) (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With Any Bleeding Event (CEC-adjudicated) [ Time Frame: Up to Day 14; Up to Day 52 ]
    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.

  2. Number of Participants With Total VTE (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    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.

  3. Number of Participants With Composite of Major and Clinically Relevant Nonmajor Bleeding (CRNM) Events (CEC-adjudicated) [ Time Frame: Up to Day 14, Up to Day 52 ]
    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.

  4. Number of Participants With Major Bleeding Events (CEC-adjudicated) [ Time Frame: Up to Day 14; Up to Day 52 ]
    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.

  5. Number of Participants With CRNM Bleeding Events (CEC-adjudicated) [ Time Frame: Up to Day 14; Up to Day 52 ]
    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.

  6. Number of Participants With Minimal Bleeding Events (CEC-adjudicated) [ Time Frame: Up to Day 14; Up to Day 52 ]
    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.

  7. Number of Participants With Major or CRNM Bleeding Events (CEC-adjudicated) [ Time Frame: Up to Day 14; Up to Day 52 ]
    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.

  8. Number of Participants With Major VTE (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    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.

  9. Number of Participants With Major VTE (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    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.

  10. Number of Participants With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    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.

  11. Number of Participants With Proximal DVT (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    Number of participants with proximal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.

  12. Number of Participants With Distal DVT (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    Number of participants with distal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.

  13. Number of Participants With Distal DVT (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    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.

  14. Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    Number of participants with nonfatal PE (adjudicated by CEC) were reported.

  15. Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    Number of participants with nonfatal PE (adjudicated by CEC) were reported.

  16. Number of Participants With Deaths (CEC-adjudicated) [ Time Frame: Up to Day 14 ]
    Number of participants with deaths (CEC-adjudicated) were reported.

  17. Number of Participants With Deaths (CEC-adjudicated) [ Time Frame: Up to Day 52 ]
    Number of participants with deaths (CEC-adjudicated) were reported.

  18. Apparent Clearance (CL/F) of JNJ-70033093 [ Time Frame: Up to Day 14 ]
    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.

  19. Apparent Volume of Distribution (V/F) of JNJ-70033093 [ Time Frame: Up to Day 14 ]
    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.

  20. Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex [ Time Frame: Up to Day 14 ]
    Impact of demographic character (sex) on CL/F was assessed.

  21. Impact of Selected Demographic: Age on CL/F [ Time Frame: Up to Day 14 ]
    Impact of age on CL/F was assessed.

  22. Impact of Selected Demographic: Weight on CL/F [ Time Frame: Up to Day 14 ]
    Impact of weight on CL/F was assessed.

  23. Impact of Selected Laboratory Values: Renal Function on CL/F [ Time Frame: Up to Day 14 ]
    Impact of renal function on CL/F was assessed. The outcome measure was reported based on CRCL.

  24. Impact of Selected Demographics: Sex on Apparent Volume of Distribution (V/F) [ Time Frame: Up to Day 14 ]
    Impact of sex on V/F was assessed.

  25. Impact of Selected Demographics : Age on V/F [ Time Frame: Up to Day 14 ]
    Impact of age on V/F was assessed.

  26. Impact of Selected Demographics : Weight on V/F [ Time Frame: Up to Day 14 ]
    Impact of weight on V/F was assessed.

  27. Impact of Selected Laboratory Values: Renal Function on V/F [ Time Frame: Up to Day 14 ]
    Impact of renal function on V/F was assessed. The outcome measure is reported based on CRCL.

  28. Trend Test for Primary Efficacy Event Rate (CEC Adjudicated) by Multiple Comparison Procedure - Modelling (MCP-Mod) Approach [ Time Frame: Up to 14 days ]
    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.

  29. Trend Test for the Composite of On-Treatment Major and Clinically Relevant Nonmajor Bleeding (CEC Adjudicated) by MCP-Mod Approach [ Time Frame: Up to 14 days ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03891524


Locations
Show Show 117 study locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:
Study Protocol  [PDF] September 10, 2019
Statistical Analysis Plan  [PDF] September 26, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03891524    
Other Study ID Numbers: CR108600
70033093THR2001 ( Other Identifier: Janssen Research & Development, LLC )
2018-004237-32 ( EudraCT Number )
First Posted: March 27, 2019    Key Record Dates
Results First Posted: July 15, 2022
Last Update Posted: July 15, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinicaltrials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu
URL: https://www.janssen.com/clinical-trials/transparency

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
Layout table for MeSH terms
Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action