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

Sponsored by:	Takeda Global Research & Development Center, Inc.
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00641732

Purpose

The purpose of this study is to determine if TAK-442 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 II

Study Type:	Interventional
Study Design:	Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study
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:

MedlinePlus related topics: Deep Vein Thrombosis Knee Replacement Pulmonary Embolism

Drug Information available for: Enoxaparin Sodium

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Composite evaluation of all-cause mortality, symptomatic and asymptomatic deep vein thrombosis, and symptomatic pulmonary embolism. [ Time Frame: Days 1, 2, 3, 4 and 10 or Final Visit ] [ Designated as safety issue: No ]
Incidence of major bleeding [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Evaluation of major venous thromboembolism (composite of symptomatic or asymptomatic proximal deep vein thrombosis, symptomatic, pulmonary embolism, and venous thromboembolism-related death) [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of symptomatic venous thromboembolism. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of proximal deep vein thrombosis. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of distal deep vein thrombosis. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of clinically significant non-major bleeding events. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of minor bleeding events. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: No ]
Evaluation of Pharmacodynamic Marker (activated factor X inhibition) [ Time Frame: Days 1, 3, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: No ]
Evaluation o Pharmacodynamic Marker (coagulation parameters prothrombin time and activated partial thromboplastin time) [ Time Frame: Days 1, 3, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: No ]
Change from Baseline in Clinical Laboratory Urinalysis values. [ Time Frame: Days 1, 3, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: Yes ]
Change from Baseline in Clinical Laboratory Hematology values. [ Time Frame: Days 1, 3, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: Yes ]
Change from Baseline in Clinical Laboratory Chemistry values. [ Time Frame: Days 1, 3, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: Yes ]
Incidence of adverse events. [ Time Frame: Days 1, 2, 3, 4, 10 or Final Visit. ] [ Designated as safety issue: Yes ]
Evaluate electrocardiogram results. [ Time Frame: Days 1 and 10 or Final Visit ] [ Designated as safety issue: Yes ]
Evaluate physical examination findings. [ Time Frame: Day 10 or Final Visit ] [ Designated as safety issue: Yes ]
Evaluate vital signs measurements. [ Time Frame: Days 1, 2, 4, 10 or Final Visit, and 30 days post last dose. ] [ Designated as safety issue: Yes ]
Evaluate Postoperative blood drainage during the hospital stay. [ Time Frame: Day 4 ] [ Designated as safety issue: Yes ]
Evaluate transfusion volume during the treatment period. [ Time Frame: Days 1, 2, 3, 4, and 10 or Final Visit ] [ Designated as safety issue: Yes ]
Plasma concentrations of TAK-442 and its metabolites (M-I, M-II) [ Time Frame: Day 3. ] [ 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
1: Experimental	Drug: TAK-442 TAK-442 40 mg, tablets, orally, once daily and TAK-442 placebo-matching tablets, orally, twice daily for up to 10 days.
2: Experimental	Drug: TAK-442 TAK-442 80 mg, tablets, orally, once daily and TAK-442 placebo-matching tablets, orally, once daily for up to 10 days.
3: Experimental	Drug: TAK-442 TAK-442 10 mg, tablets, orally, twice daily and TAK-442 placebo-matching tablets, orally, twice daily for up to 10 days.
4: Experimental	Drug: TAK-442 TAK-442 20 mg, tablets, orally, twice daily and TAK-442 placebo-matching tablets, orally, twice daily for up to 10 days.
5: Experimental	Drug: TAK-442 TAK-442 40 mg, tablets, orally, twice daily and TAK-442 placebo-matching tablets, orally, twice daily for up to 10 days.
6: Experimental	Drug: TAK-442 TAK-442 80 mg, tablets, orally, twice daily for up to 10 days.
7: Active Comparator	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

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

Show 64 Study Locations

Sponsors and Collaborators

Takeda Global Research & Development Center, Inc.

Investigators

Study Director:

Executive Medical Director Clinical Science

Takeda Global Research & Development Center, Inc.

More Information

No publications provided

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	TAK-442_201
Study First Received:	March 18, 2008
Last Updated:	December 19, 2008
ClinicalTrials.gov Identifier:	NCT00641732 History of Changes
Health Authority:	United States: Food and Drug Administration; Canada: Health Canada

Keywords provided by Takeda Global Research & Development Center, Inc.:

venous thromboembolism
oral anticoagulant
direct factor Xa inhibitor
total knee replacement
drug therapy

Study placed in the following topic categories:

Fibrin Modulating Agents
Embolism and Thrombosis
Anticoagulants
Embolism
Vascular Diseases
Fibrinolytic Agents

Cardiovascular Agents
Venous Thromboembolism
Antithrombin III
Thrombosis
Thromboembolism
Enoxaparin

Additional relevant MeSH terms:

Anticoagulants
Molecular Mechanisms of Pharmacological Action
Hematologic Agents
Vascular Diseases
Fibrinolytic Agents
Cardiovascular Agents
Venous Thromboembolism
Thromboembolism

Thrombosis
Pharmacologic Actions
Enoxaparin
Embolism and Thrombosis
Fibrin Modulating Agents
Therapeutic Uses
Cardiovascular Diseases

ClinicalTrials.gov processed this record on September 10, 2009