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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: ISIS-FXIRx Dose #2
* Drug: ISIS-FXIRx Dose #3
* Drug: Enoxaparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ISIS-FXIRx Dose 2<br>Group B: ISIS-FXIRx Dose #2 | Drug: ISIS-FXIRx Dose #2<br>* Group B: ISIS-FXIRx dose #2 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.<br>* Other names: ISIS-FXIRx;|
| Experimental: ISIS-FXIRx Dose 3<br>Group C: ISIS-FXIRx Dose #3 | Drug: ISIS-FXIRx Dose #3<br>* Group C: ISIS-FXIRx dose #3 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.<br>* Other names: ISIS-FXIRx;|
| Active Comparator: Enoxaparin<br>Enoxaparin (40mg) | Drug: Enoxaparin<br>* Enoxaparin (40mg) will be administered by subcutaneous injection the evening prior to total knee arthroplasty (optionally), 6 to 8 hours after surgery, followed by daily injections for at least 8 additional days post surgery (a total of at least 9 consecutive days). [Except for Canadian region, in which the subcutaneous injection of enoxaparin the evening prior to total knee arthroplasty is expected, resulting in a total of at least 10 consecutive days of enoxaparin.]<br>* Other names: Clexane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary efficacy outcome | Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death. | up to 12 days post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary efficacy outcome | All DVTs and PEs up to 4 weeks after bilateral venography | 1st dose to up to Day 76 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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total knee arthroplasty, Prophylaxis