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

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.

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.