Active Comparator-Controlled Study to Assess Safety and Efficacy of ISIS-FXIRx in Total Knee Arthroplasty

An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty

The purpose of this study is:

• To assess the safety and efficacy profile of ISIS-FXIRx, including incidence of bleeding and VTE, in patients undergoing total knee arthroplasty.
• To compare the efficacy and safety profile of ISIS-FXIRx in patients who achieve less than or equal to 0.2 U/mL FXI activity levels to that of enoxaparin.

Inclusion Criteria:

• Give written informed consent
• Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, must use contraception
• Undergoing elective, primary unilateral total knee arthroplasty

Exclusion Criteria:

• Body weight <50 kg

• Patients at increased risk of bleeding. History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year.

• History of excessive intra- or direct post operative bleeding or a traumatic spinal or epidural anesthesia

• Brain, spinal, or ophthalmologic surgery within the past 3 months

• History of clinically significant liver disease in the past year

• Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values

  • aPTT or PT or INR >ULN
  • Factor IX activity <LLN
  • Factor VIII activity, vWF antigen or Ristocetin cofactor activity <0.5 U/mL
  • FXI activity <0.3 U/mL
  • Urine protein or blood persistently positive by dipstick. In the event of positive test results, eligibility may be confirmed with urine microscopy or 24 hour urine protein measurement as applicable
  • ALT or AST >1.5 x ULN
  • Total bilirubin >ULN
  • Platelet count <150,000 (or history of thrombocytopenia)

• Hypersensitivity to enoxaparin

• Anticipated concomitant use of anticoagulants/antiplatelet agents or the NSAID nimesulide that may affect study outcome or any other drug influencing coagulation (except low dose aspirin and short acting NSAIDs with a half-life <20 hours) at least 7 days before surgery or during treatment with ISIS Rx.

• Anticipated use of indwelling intrathecal or epidural catheters

• Anemia at Screening

• Have any other conditions which could interfere with the patient participating in or completing the study