Prevention of Venous Thromboembolism in Patients Undergoing Elective Total Knee Replacement Surgery - Clinical Trial for Venous Thromboembolism | NCT00331838

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Semuloparin sodium

Placebo (for Enoxaparin sodium)

Enoxaparin sodium

Placebo (for Semuloparin sodium)

About this trial

This is an interventional prevention trial for Venous Thromboembolism focused on measuring Prevention, Venous Thrombosis, Orthopedic Surgery

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

Semuloparin 5 mg

Semuloparin 10 mg

Semuloparin 20 mg

Semuloparin 40 mg

Semuloparin 60 mg

Enoxaparin 40 mg

Placebo pre-op / Semuloparin 20 mg

Placebo pre-op / Semuloparin 40 mg

Arm Description

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

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

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

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

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

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

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

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Number of Participants Who Experienced DVT

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.

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).

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.

Full Information

NCT ID

NCT00331838

First Posted

May 18, 2006

Last Updated

January 14, 2013

Sponsor

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT00331838

Brief Title

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

Acronym

TREK

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2013

Overall Recruitment Status

Completed

Study Start Date

May 2006 (undefined)

Primary Completion Date

June 2007 (Actual)

Study Completion Date

June 2007 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Venous Thromboembolism

Keywords

Prevention, Venous Thrombosis, Orthopedic Surgery

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

705 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Semuloparin 5 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Semuloparin 10 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Semuloparin 20 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Semuloparin 40 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Semuloparin 60 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Enoxaparin 40 mg

Arm Type

Active Comparator

Arm Description

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

Arm Title

Placebo pre-op / Semuloparin 20 mg

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo pre-op / Semuloparin 40 mg

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Semuloparin sodium

Other Intervention Name(s)

AVE5026

Intervention Description

0.8 mL solution in Type I amber glass vials Subcutaneous injection

Intervention Type

Drug

Intervention Name(s)

Placebo (for Enoxaparin sodium)

Intervention Description

0.4 mL solution in ready-to-use prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection

Intervention Type

Drug

Intervention Name(s)

Enoxaparin sodium

Other Intervention Name(s)

Lovenox®

Intervention Description

0.4 mL solution in ready-to-use pre-filled syringe Subcutaneous injection

Intervention Type

Drug

Intervention Name(s)

Placebo (for Semuloparin sodium)

Intervention Description

0.8 ml solution in type I amber glass vials strictly identical in appearance containing the same volume but without active component Subcutaneous injection

Primary Outcome Measure Information:

Title

Number of Participants Who Experienced Venous Thromboembolism Event (VTE) or VTE-related Death

Description

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).

Time Frame

From surgery to Day 11 or the day of mandatory venography, whichever came first

Secondary Outcome Measure Information:

Title

Number of Participants Who Experienced DVT

Time Frame

From surgery up to Day 11 or the day of mandatory venography, whichever came first

Title

Number of Participants Who Experienced Symptomatic VTE

Description

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.

Time Frame

From surgery up to Day 11 or the day of mandatory venography, whichever came first

Title

Number of Participants Who Experienced Bleedings

Description

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).

Time Frame

From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)

Title

Number of Participants Who Required Initiation of Curative Anticoagulant or Thrombolytic Treatment After VTE Assessment

Description

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.

Time Frame

From surgery up to Day 11 or the day of mandatory venography, whichever came first

Other Pre-specified Outcome Measures:

Title

Number of Deaths

Description

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).

Time Frame

From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)

Title

Platelets Count: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA]

Description

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.

Time Frame

From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)

Title

Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA]

Description

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.

Time Frame

From 1st study drug injection up to 3 days after last study drug injection (median duration of approximately 11 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael LASSEN, MD

Organizational Affiliation

Hoersholm Hospital (Denmark)

Official's Role

Study Chair

Facility Information:

Facility Name