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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03891524
Recruitment Status : Recruiting
First Posted : March 27, 2019
Last Update Posted : November 15, 2019
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 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
Estimated Primary Completion Date : March 23, 2021
Estimated Study Completion Date : March 23, 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) [ Time Frame: Up to 14 days ]
    Total VTE is defined as the composite of 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 [ Time Frame: Up to 14 days ]
    Any bleeding event is defined as the composite of major, clinically relevant nonmajor, and/or minimal bleeding events.

  2. Number of Participants with Total VTE [ Time Frame: Up to Week 6 ]
    Total VTE is defined as the composite of 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.

  3. Number of Participants with any Bleeding Event [ Time Frame: Up to Week 6 ]
    Any bleeding event is defined as the composite of major, clinically relevant nonmajor, and/or minimal bleeding events.

  4. Number of Participants with Composite of Major and Clinically Relevant Nonmajor Bleeding Events [ Time Frame: Up to Week 6 ]
    Bleeding events composite of major and clinically relevant nonmajor events will be assessed through Week 6.

  5. Number of Participants with Major Bleeding Events [ Time Frame: Up to Week 6 ]
    Major bleeding is defined as: Fatal bleeding; bleeding that is symptomatic and occurs in a critical area or organ and/or; extrasurgical site bleeding causing a fall in hemoglobin level of 20 gram per liter (g/L) (1.24 millimole per liter [mmol/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 the bleeding, and/or; surgical site bleeding that requires a second intervention open, arthroscopic, endovascular, or a hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability.

  6. Number of Participants with Clinically Relevant Nonmajor Bleeding Events [ Time Frame: Up to Week 6 ]
    Clinically relevant nonmajor bleeding is defined as acute clinically overt bleeding which does not satisfy additional criteria required for the bleeding event to be defined as a major bleeding event and meets at least 1 of the following criteria: Epistaxis (nose bleed), Gastrointestinal bleed, Hematuria, Bruising/ecchymosis, Hemoptysis, Hematoma.

  7. Number of Participants with Minimal Bleeding Events [ Time Frame: Up to Week 6 ]
    Any overt bleeding not meeting major or clinically relevant nonmajor criteria will be assessed as minimal bleeding.

  8. Number of Participants with Major VTE [ Time Frame: Up to 14 days and up to Week 6 ]
    Major VTE is a composite of asymptomatic or symptomatic proximal DVT, PE, or any death.

  9. Number of Participants with Proximal and/or Distal Deep Vein Thrombosis (DVT) [ Time Frame: Up to 14 days and up to Week 6 ]
    Number of Participants with Proximal and/or Distal Deep Vein Thrombosis (DVT) will be assessed. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic.

  10. Number of Participants with Nonfatal Pulmonary Embolism (PE) [ Time Frame: Up to 14 days and up to Week 6 ]
    Number of Participants with Nonfatal Pulmonary Embolism (PE) will be assessed. For all participants with symptoms of PE, spiral computed tomography (CT), pulmonary angiography, or perfusion/ventilation lung scintigraphy combined with chest radiography will be performed.

  11. Number of Participants with Deaths [ Time Frame: Up to 14 days and up to Week 6 ]
    Number of participants with deaths will be reported.

  12. Apparent Clearance (CL/F) of JNJ-70033093 [ Time Frame: Day 1: 2, 4, and 12 hours postdose; Day 2; Day 4: 0, 2, 4, and 12 hours postdose; Day 7; and Day 10 to Day 14 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

  13. Apparent Volume of Distribution (V/F) of JNJ-70033093 [ Time Frame: Day 1: 2, 4, and 12 hours postdose; Day 2; Day 4: 0, 2, 4, and 12 hours postdose; Day 7; and Day 10 to Day 14 ]
    V/F is 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.

  14. Impact of Selected Demographics or Laboratory Values (Example [e.g.] sex, age, Weight) on Apparent Clearance (CL/F) [ Time Frame: Day 1: 2, 4, and 12 hours postdose; Day 2; Day 4: 0, 2, 4, and 12 hours postdose; Day 7; and Day 10 to Day 14 ]
    Impact of selected demographics or laboratory values (e.g. sex, age, weight) on Apparent Clearance (CL/F) will be assessed.

  15. Impact of Selected Demographics or Laboratory Values (e.g. sex, age, Weight) on Apparent Volume of Distribution (V/F) [ Time Frame: Day 1: 2, 4, and 12 hours postdose; Day 2; Day 4: 0, 2, 4, and 12 hours postdose; Day 7; and Day 10 to Day 14 ]
    Impact of selected demographics or laboratory values (e.g. sex, age, weight) on V/F will be assessed.

  16. Relationship between JNJ-70033093 Dose Levels with Total VTE [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 dose levels with total VTE will be determined using a multiple comparison procedures and modeling (MCP-Mod) approach.

  17. Relationship Between JNJ-70033093 Dose Levels with Composite of Major or Clinically Relevant Nonmajor Bleeding Events [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 dose levels with composite of major or clinically relevant nonmajor bleeding events will be determined using a MCP-Mod approach.

  18. Relationship between JNJ-70033093 Dose Levels with Major Bleeding Events [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 dose levels with major bleeding events will be determined using a MCP-Mod approach.

  19. Relationship between JNJ-70033093 Dose Levels with Clinically Relevant Nonmajor Bleeding Events [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 dose levels with clinically relevant nonmajor bleeding events will be determined using a MCP-Mod approach.

  20. Relationship between JNJ-70033093 Dose Levels with Minimal Bleeding Events [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 dose levels with minimal bleeding events will be determined using a MCP-Mod approach.

  21. Relationship Between JNJ-70033093 Exposure with Total VTE [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 exposure with total VTE, determined using Exposure-Response analysis.

  22. Relationship Between JNJ-70033093 Exposure with Composite of Major or Clinically Relevant Nonmajor Bleeding Events [ Time Frame: Up to 14 days ]
    Relationship between JNJ-70033093 exposure with composite of major or clinically relevant nonmajor bleeding events, determined using Exposure-Response analysis.



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.


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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


Contacts
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Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

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Sponsors and Collaborators
Janssen Research & Development, LLC
Bristol-Myers Squibb
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03891524     History of Changes
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
Last Update Posted: November 15, 2019
Last Verified: November 2019
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

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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