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

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

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.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Semuloparin sodium; Drug: Placebo (for Enoxaparin sodium); Drug: Enoxaparin sodium; Drug: Placebo (for Semuloparin sodium)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 705
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Bulgaria
  • Sofia, Bulgaria
    • Sanofi-Aventis Administrative Office
• Chile
  • Santiago, Chile
    • Sanofi-Aventis Administrative Office
• Colombia
  • Santafe de Bogota, Colombia
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• Greece
  • Athens, Greece
    • Sanofi-Aventis Administrative Office
• Malaysia
  • Kuala Lumpur, Malaysia
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis Administrative Office
• Philippines
  • Makati City, Philippines
    • Sanofi-Aventis Administrative Office
• Poland
  • Warszawa, Poland
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Romania
  • Bucuresti, Romania
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Taiwan
  • Taipei, Taiwan
    • Sanofi-Aventis Administrative Office
• Thailand
  • Bangkok, Thailand
    • Sanofi-Aventis Administrative Office
• Turkey
  • Istanbul, Turkey
    • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semuloparin 5 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Semuloparin 10 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Semuloparin 20 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Semuloparin 40 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Semuloparin 60 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Active Comparator: Enoxaparin 40 mg; 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; 0.4 mL solution in ready-to-use pre-filled syringe Subcutaneous injection; Other Names: Lovenox®; Drug: Placebo (for Semuloparin sodium); 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Placebo pre-op / Semuloparin 20 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection; Drug: Placebo (for Semuloparin sodium); 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection
Experimental: Placebo pre-op / Semuloparin 40 mg; 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; 0.8 mL solution in Type I amber glass vials Subcutaneous injection; Other Names: AVE5026; Drug: Placebo (for Enoxaparin sodium); 0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection; Drug: Placebo (for Semuloparin sodium); 0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Deaths	All deaths were centrally and blindly reviewed by the CIAC and classified as "Fatal PE", "PE not excluded", "Fatal bleeding" and "Death not associated with VTE or bleeding" based on relevant documentation (e.g. autopsy report).	From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)
Platelets Count: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA]	PCSA are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Threshold for platelet counts was defined as <100 Giga/L.	From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA]	Thresholds were defined as follows: Alanine Aminotransferase [ALAT] >3 Upper Normal Limit [ULN];; Total Bilirubin [TB] ≥34 μmol/L;; ALAT ≥3 ULN and TB ≥34 μmol/L.	From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Chair: Michael LASSEN, MD, Hoersholm Hospital (Denmark)

Publications and helpful links

General Publications

• Lassen MR, Dahl OE, Mismetti P, Destree D, Turpie AG. AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery--TREK: a dose-ranging study. J Thromb Haemost. 2009 Apr;7(4):566-72. doi: 10.1111/j.1538-7836.2009.03301.x. Epub 2009 Jan 24.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): June 1, 2007
• Study Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: May 18, 2006
• First Submitted That Met QC Criteria: May 30, 2006
• First Posted (Estimate): May 31, 2006

Study Record Updates

• Last Update Posted (Estimate): January 15, 2013
• Last Update Submitted That Met QC Criteria: January 14, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Prevention; Orthopedic Surgery; Venous Thrombosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Heparin, Low-Molecular-Weight; Enoxaparin sodium; Semuloparin
• Other Study ID Numbers: DRI6243; 2005-006202-26 (EudraCT Number)