Efficacy and Safety of TAK-442 in Subjects Undergoing Total Knee Replacement

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00641732
First received: March 18, 2008
Last updated: February 1, 2012
Last verified: February 2012
  Purpose

The purpose of this study is to determine if TAK-442, once daily (QD) or twice daily (BID), is as safe and effective as enoxaparin in preventing the development of blood clots after knee replacement surgery.


Condition Intervention Phase
Venous Thromboembolism
Drug: TAK-442
Drug: Enoxaparin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase 2, Randomized, Active Comparator-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of TAK-442 in Subjects Undergoing Total Knee Replacement

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Composite evaluation of All-Cause Mortality, Symptomatic and Asymptomatic Deep Vein Thrombosis and Symptomatic Pulmonary Embolism. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Incidence of Major Bleeding. [ Time Frame: Day 10. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluation of Major Venous Thromboembolism (composite of Symptomatic or Asymptomatic Proximal Deep Vein Thrombosis, Symptomatic Objectively Confirmed Pulmonary Embolism, and Venous Thromboembolism-Related Death). [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Evaluation of Symptomatic Venous Thromboembolism. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Evaluation of Proximal Deep Vein Thrombosis. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Evaluation of Distal Deep Vein Thrombosis. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Evaluation of clinically significant Non-Major Bleeding events. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]
  • Evaluation of Minor Bleeding events. [ Time Frame: Day 10. ] [ Designated as safety issue: No ]

Enrollment: 1045
Study Start Date: October 2007
Study Completion Date: October 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TAK-442 40 mg QD Drug: TAK-442
TAK-442 40 mg, tablets, orally, once daily for up to 10 days.
Experimental: TAK-442 80 mg QD Drug: TAK-442
TAK-442 80 mg, tablets, orally, once daily for up to 10 days.
Experimental: TAK-442 10 mg BID Drug: TAK-442
TAK-442 10 mg, tablets, orally, twice daily for up to 10 days.
Experimental: TAK-442 20 mg BID Drug: TAK-442
TAK-442 20 mg, tablets, orally, twice daily for up to 10 days.
Experimental: TAK-442 40 mg BID Drug: TAK-442
TAK-442 40mg, tablets, orally, twice daily for up to 10 days.
Experimental: TAK-442 80 mg BID Drug: TAK-442
TAK-442 80 mg, tablets, orally, twice daily for up to 10 days.
Active Comparator: Enoxaparin 30 mg BID Drug: Enoxaparin
Enoxaparin 30 mg, syringe, subcutaneous injection, twice daily for up to 10 days.

Detailed Description:

Takeda Global Research & Development Center, Inc. is developing the compound TAK-442 as a candidate for the secondary prevention of atherothrombotic events in patients with acute coronary syndromes. TAK-442 is an oral inhibitor of activated factor X within the blood coagulation cascade.

Due to its critical role in propagating the coagulation cascade, activated factor X is now considered to be a therapeutic aim in the development of anticoagulant drugs. Therefore activated factor X inhibitors, are among the agents under investigation as treatments for the spectrum of thromboembolic diseases involving either the arterial or the venous system.

Short term anticoagulation is often used for the prevention of venous thromboembolism. Patients undergoing major orthopedic surgery are at particularly high risk of venous thromboembolism after surgery. Consequently, such patients are routinely given anticoagulant medication after surgery. Although parenteral (injectable) drugs, such as enoxaparin or fondaparinux, can be used for this indication, the need for subcutaneous injection is problematic once patients are discharged from hospital. With the push for shorter hospital stays, this issue is of increasing concern. Therefore, there is a need for new oral anticoagulants. Although warfarin can be used for out of hospital prophylaxis, the need for coagulation monitoring and dose adjustments complicates its use. The new oral anticoagulants have the potential to overcome this problem because they can be given in fixed doses without the need for coagulation monitoring.

The purpose of the current study is to evaluate the antithrombotic effect of TAK-442 in patients undergoing elective total knee replacement surgery. This study will be the first TAK-442 trial in patients.

Individuals who want to participate in this study will be required to provide written informed consent. Study participation is anticipated to be approximately 2.25 months. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations, electrocardiograms and bilateral venogram. Outside of the study center, participants randomized to enoxaparin will be required to administer study medication subcutaneously with a syringe.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Scheduled to undergo elective, unilateral, primary, total knee replacement.
  • Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
  • Screening laboratory tests (including clinical chemistry, hematology, and complete urinalysis) are within the reference range for the testing laboratory or are determined not to compromise subject safety by the investigator.

Exclusion Criteria

  • Received TAK-442 in a previous clinical study or as a therapeutic agent.
  • Body weight greater than 150 kg.
  • Known bleeding diathesis (including Von Willebrand's disease or Hemophilia A or B).
  • History of intracerebral, intraocular, or gastrointestinal bleeding, or active gastric or duodenal ulceration, within the 6 months prior to Randomization.
  • Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including throughout the treatment period of the study due to an increased risk of bleeding, and should be stopped at least 5 days prior to surgery and in accordance with the product information:

    • Parenteral anticoagulants
    • Unfractionated heparin
    • Low molecular weight heparin (eg, dalteparin, non-study enoxaparin)
    • Direct thrombin inhibitors (eg, bivalirudin, argatroban)
    • Factor Xa inhibitors (eg, fondaparinux)
    • Oral anticoagulants
    • Warfarin
    • Anisindione
    • Antiplatelet drugs
    • Aspirin greater than 162 mg/day
    • Clopidogrel
    • Ticlopidine
    • Cilostazol
    • Dipyridamole
    • Glycoprotein IIb/IIIa inhibitors (eg, abciximab, eptifibatide)
    • NSAIDs with a half life greater than or equal to 17 hours
    • Meloxicam
    • Fibrinolytic agents
    • tPA (alteplase, reteplase, tenecteplase)
  • History of major surgery within 3 months prior to randomization; or deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident, or transient ischemic attack within 6 months prior to randomization.
  • History of hypersensitivity or allergies to other activated factor X inhibitors or enoxaparin (or other low molecular weight heparins).
  • Condition prohibiting bilateral venography.
  • Has had multiple or traumatic epidural or spinal punctures immediately prior to randomization (defined as grossly bloody or greater than 3 attempted cannulations).
  • Requires use of an indwelling epidural catheter for post-operative analgesia.
  • Severe hypertension defined as systolic blood pressure greater than 180 mmHg or diastolic blood pressure greater than 110 mmHg at Screening.
  • Moderate to severe renal dysfunction or disease (based on calculated creatinine clearance less than 45 mL/min/1.73 m2) at Screening.
  • Alanine aminotransferase level greater than 2.0 times the upper limit of normal, active liver disease, or jaundice at Screening.
  • Anemia (hemoglobin less than 10.0 g per dL) or thrombocytopenia (platelet count less than 100 times 103 per uL) at screening.
  • Taking aspirin greater than 162 mg per day.
  • Abuses drugs (defined as any illicit drug use) or alcohol.
  • History of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.)
  • Currently participating in another investigational study or has participated in an investigational study within 30 days prior to Screening.
  • Any other serious disease or condition at Screening or Randomization that would compromise subject safety or make it difficult to successfully manage and follow the subject according to the protocol.
  • Requires the use of pneumatic compression post-operatively.
  • Known inherited thrombophilic disorder such as the factor V Leiden or prothrombin gene mutations or deficiencies of antithrombin, protein C, or protein S.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00641732

  Hide Study Locations
Locations
United States, Alabama
Birmingham, Alabama, United States
Tuscaloosa, Alabama, United States
United States, Arizona
Phoenix, Arizona, United States
United States, Arkansas
Little Rock, Arkansas, United States
United States, California
Bakersfield, California, United States
Fountain Valley, California, United States
Long Beach, California, United States
Montclair, California, United States
Oceanside, California, United States
Vista, California, United States
Yuba City, California, United States
United States, Colorado
Aurora, Colorado, United States
Centennial, Colorado, United States
Denver, Colorado, United States
United States, Florida
Bay Pines, Florida, United States
Clearwater, Florida, United States
DeLand, Florida, United States
Gulf Breeze, Florida, United States
Hollywood, Florida, United States
Pinellas Park, Florida, United States
Tamarac, Florida, United States
United States, Georgia
Atlanta, Georgia, United States
United States, Idaho
Boise, Idaho, United States
Meridian, Idaho, United States
United States, Illinois
Springfield, Illinois, United States
United States, Maryland
Towson, Maryland, United States
United States, North Carolina
Charlotte, North Carolina, United States
Greensboro, North Carolina, United States
United States, Ohio
Cincinnati, Ohio, United States
United States, Oklahoma
Tulsa, Oklahoma, United States
United States, Pennsylvania
Altoona, Pennsylvania, United States
Johnstown, Pennsylvania, United States
United States, South Carolina
Charleston, South Carolina, United States
United States, Texas
Dallas, Texas, United States
Grapenne, Texas, United States
Lubbock, Texas, United States
San Antonio, Texas, United States
United States, Washington
Spokane, Washington, United States
Canada, Alberta
Edmonton, Alberta, Canada
Red Deer, Alberta, Canada
Canada, British Columbia
Kelowna, British Columbia, Canada
Canada, Manitoba
Winnipeg, Manitoba, Canada
Canada, New Brunswick
Fredericton, New Brunswick, Canada
St. John, New Brunswick, Canada
Canada, Nova Scotia
Dartmouth, Nova Scotia, Canada
Canada, Ontario
Ajax, Ontario, Canada
Burlington, Ontario, Canada
Cambridge, Ontario, Canada
Chatham, Ontario, Canada
Guelph, Ontario, Canada
Kitchener, Ontario, Canada
Newmarket, Ontario, Canada
Niagra Falls, Ontario, Canada
Oakville, Ontario, Canada
Oshawa, Ontario, Canada
Ottawa, Ontario, Canada
Sarnia, Ontario, Canada
Scarborough, Ontario, Canada
St. Catherines, Ontario, Canada
Sudbury, Ontario, Canada
Thunder Bay, Ontario, Canada
Windsor, Ontario, Canada
Canada, Quebec
Montreal, Quebec, Canada
Canada
Charlottetown, Canada
Sponsors and Collaborators
Takeda
Investigators
Study Director: Executive Medical Director Clinical Science Takeda
  More Information

Publications:
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00641732     History of Changes
Other Study ID Numbers: TAK-442_201, U1111-1115-9359
Study First Received: March 18, 2008
Last Updated: February 1, 2012
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Takeda:
venous thromboembolism
oral anticoagulant
direct factor Xa inhibitor
total knee replacement
drug therapy

Additional relevant MeSH terms:
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism and Thrombosis
Thrombosis
Vascular Diseases

ClinicalTrials.gov processed this record on October 21, 2014