Prevention of Venous Thromboembolism in Patients Undergoing Elective Total Knee Replacement Surgery

Study Overview
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Brief Summary
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The primary objective was to demonstrate the dose-response of Semuloparin sodium (AVE5026) for the prevention of Venous Thromboembolism [VTE] in patients undergoing total knee replacement [TKR] surgery. Secondary objectives were to evaluate the safety (incidence of major bleeding) of AVE5026, to document the efficacy and safety of AVE5026 post-operative regimens, and to assess the pharmacokinetic parameters of AVE5026.

Detailed Description
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The randomization had to take place before the first study drug injection. The total duration of observation per participant was 27-33 days from surgery broken down as follows: 4 to 10-day double-blind treatment period; Follow-up period up to Day 30 ± 3 after surgery. Mandatory bilateral venography of the lower limbs had to be performed between 5 to 11 days after surgery.

Official Title
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A Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel Group, Dose Response Study of Subcutaneous AVE5026 With an Enoxaparin Calibrator Arm in the Prevention of Venous Thromboembolism in Patients Undergoing Elective Total Knee Replacement Surgery

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Semuloparin sodium
* Drug: Placebo (for Enoxaparin sodium)
* Drug: Enoxaparin sodium
* Drug: Placebo (for Semuloparin sodium)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient scheduled to undergo elective total knee replacement or revision of a primary procedure performed ≥ 6 months prior to study entry. Exclusion Criteria: Any major orthopedic surgery in the 3 months prior to study entry; Clinical signs or symptoms of DVT or PE within the last 12 months or known post-phlebitic syndrome; Known sensitivity to iodine or contrast dyes; Recent stroke or myocardial infarction; High risk of bleeding; Treatment with other anti-thrombotic agents within 7 days prior to surgery; Any contra-indication to Unfractionated Heparin or Low Molecular Weight Heparin; Pregnant or nursing woman, or woman of childbearing potential who is not using an effective contraceptive method. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semuloparin 5 mg<br>Semuloparin sodium 5 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Semuloparin 10 mg<br>Semuloparin sodium 10 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Semuloparin 20 mg<br>Semuloparin sodium 20 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Semuloparin 40 mg<br>Semuloparin sodium 40 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Semuloparin 60 mg<br>Semuloparin sodium 60 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Active Comparator: Enoxaparin 40 mg<br>Enoxaparin sodium 40 mg + Placebo (for Semuloparin sodium) once daily for 4-10 days with an initial dose given 12 hours before or 8 hours after surgery depending on the willingness of the investigator | Drug: Enoxaparin sodium<br>* 0.4 mL solution in ready-to-use pre-filled syringe Subcutaneous injection<br>* Other names: Lovenox®;Drug: Placebo (for Semuloparin sodium)<br>* 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Placebo pre-op / Semuloparin 20 mg<br>Placebo (for Semuloparin sodium) + Placebo (for Enoxaparin sodium) 12 hours before surgery then, Semuloparin sodium 20 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 8 hours after surgery | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>Drug: Placebo (for Semuloparin sodium)<br>* 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|
| Experimental: Placebo pre-op / Semuloparin 40 mg<br>Placebo (for Semuloparin sodium) + Placebo (for Enoxaparin sodium) 12 hours before surgery then, Semuloparin sodium 40 mg + Placebo (for Enoxaparin sodium) once daily for 4-10 days with an initial dose given 8 hours after surgery | Drug: Semuloparin sodium<br>* 0.8 mL solution in Type I amber glass vials Subcutaneous injection<br>* Other names: AVE5026;Drug: Placebo (for Enoxaparin sodium)<br>* 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>Drug: Placebo (for Semuloparin sodium)<br>* 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Venous Thromboembolism Event (VTE) or VTE-related Death | VTE included any Deep Vein Thrombosis [DVT] identified on mandatory venography of the lower limbs; symptomatic DVT and/or non-fatal pulmonary embolism [PE] before mandatory examination; VTE related deaths included fatal PE or deaths which could not be attributed to a documented cause and for which PE could not be ruled out. All events were to be confirmed by a Central Independent Adjudication Committee [CIAC] based on venographies, scheduled or unscheduled, and other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography, autopsy report, etc). | From surgery to Day 11 or the day of mandatory venography, whichever came first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced DVT |  | From surgery up to Day 11 or the day of mandatory venography, whichever came first | 
| Number of Participants Who Experienced Symptomatic VTE | Symptomatic VTE included: suspected DVT confirmed by the CIAC based on compression ultrasonography or venography; suspected PE confirmed by the CIAC based on perfusion/ventilation lung scan, pulmonary angiography or spiral computerized tomography. | From surgery up to Day 11 or the day of mandatory venography, whichever came first | 
| Number of Participants Who Experienced Bleedings | Bleedings were centrally and blindly reviewed by the CIAC and classified as: Major (fatal bleeding, bleeding that was retroperitoneal or intracranial or that involved any other critical organ (e.g. eye, adrenal gland, pericardium or spine), surgical site bleeding leading to intervention, non-surgical site bleeding requiring surgical intervention or with a bleeding index ≥2); Minor (overt bleeding considered more than expected but not meeting the criteria for major bleeding); Criteria for bleeding event not satisfied (not meeting the criteria for major or minor bleeding). | From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days) | 
| Number of Participants Who Required Initiation of Curative Anticoagulant or Thrombolytic Treatment After VTE Assessment | Initiation of curative anticoagulant or thrombolytic treatment after VTE assessment was defined from investigator's answers to questions asked after diagnostic tests for suspected VTE and/or the mandatory venography. | From surgery up to Day 11 or the day of mandatory venography, whichever came first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention, Venous Thrombosis, Orthopedic Surgery