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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00331838
First received: May 18, 2006
Last updated: January 14, 2013
Last verified: January 2013
History of Changes
  Purpose

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.


Condition Intervention Phase
Venous Thromboembolism
 Drug: Semuloparin sodium
Drug: Placebo (for Enoxaparin sodium)
Drug: Enoxaparin sodium
Drug: Placebo (for Semuloparin sodium)
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Number of Participants Who Experienced Venous Thromboembolism Event (VTE) or VTE-related Death [ Time Frame: From surgery to Day 11 or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Number of Participants Who Experienced DVT [ Time Frame: From surgery up to Day 11 or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]
  • Number of Participants Who Experienced Symptomatic VTE [ Time Frame: From surgery up to Day 11 or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]

    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.

  • Number of Participants Who Experienced Bleedings [ Time Frame: From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days) ] [ Designated as safety issue: Yes ]

    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).

  • Number of Participants Who Required Initiation of Curative Anticoagulant or Thrombolytic Treatment After VTE Assessment [ Time Frame: From surgery up to Day 11 or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Number of Deaths [ Time Frame: From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days) ] [ Designated as safety issue: Yes ]
    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).

  • Platelets Count: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days) ] [ Designated as safety issue: Yes ]
    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.

  • Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days) ] [ Designated as safety issue: Yes ]

    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.


Enrollment: 705
Study Start Date: May 2006
Study Completion Date: June 2007
Primary Completion Date: June 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00331838

  Show 19 Study Locations
Sponsors and Collaborators
Sanofi
Investigators
Study Chair: Michael LASSEN, MD Hoersholm Hospital (Denmark)
  More Information

Publications:

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00331838     History of Changes
Other Study ID Numbers: DRI6243, 2005-006202-26
Study First Received: May 18, 2006
Last Updated: January 14, 2013
Health Authority: Denmark: Danish Medicines Agency
Spain: Spanish Agency of Medicines
Poland: Ministry of Health

Keywords provided by Sanofi:
Prevention
Venous Thrombosis
Orthopedic Surgery

Additional relevant MeSH terms:
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Thrombosis
Enoxaparin
Heparin, Low-Molecular-Weight
 Heparin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on May 23, 2013