Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Thromboembolism in Patients Undergoing Elective Knee Replacement Surgery (SAVE-KNEE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00718224
First received: July 17, 2008
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

The primary objective was to compare the efficacy of Semuloparin sodium (AVE5026) with Enoxaparin for the prevention of Venous Thromboembolic Events [VTE] in patients undergoing elective knee replacement surgery.

The secondary objectives were to evaluate the safety of AVE5026 in patients undergoing elective knee replacement surgery, and to document AVE5026 exposure in this population.


Condition Intervention Phase
Venous Thromboembolism
Drug: Semuloparin sodium
Drug: Enoxaparin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Multinational, Multicenter, Randomized, Double-blind Study Comparing the Efficacy and Safety of Semuloparin (AVE5026) With Enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Elective Knee Replacement Surgery

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Percentage of Participants Who Experienced Venous Thromboembolism Event (VTE) or All-cause Death [ Time Frame: From randomization up to 10 days after surgery or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]

    VTE included any proximal or distal Deep Vein Thrombosis [DVT] (symptomatic or not) and non-fatal Pulmonary Embolism [PE] as confirmed by a Central Independent Adjudication Committee [CIAC] after central and blind review of mandatory bilateral venograms and diagnostic tests for VTE.

    All-cause deaths included fatal PE and deaths for other reason than PE.



Secondary Outcome Measures:
  • Percentage of Participants Who Experienced "Major" VTE or All-cause Death [ Time Frame: From randomization up to 10 days after surgery or the day of mandatory venography, whichever came first ] [ Designated as safety issue: No ]
    "major" VTE included any proximal DVT, symptomatic distal DVT and non-fatal PE as confirmed by the CIAC.

  • Percentage of Participants Who Experienced Clinically Relevant Bleedings [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]

    Bleedings were centrally and blindly reviewed by the CIAC and classified as:

    • "major" (fatal, in a critical area/organ, causing a post-operative drop in hemoglobin ≥2 g/dL or requiring post-operative transfusion ≥2 units of blood, leading to an invasive diagnostic or therapeutic intervention, or associated with circulatory decompensation);
    • "clinically relevant non-major" (skin hematoma or epistaxis requiring surgical/medical intervention/treatment, macroscopic hematuria, or overt bleeding requiring specific attention by healthcare professional);
    • "Non-clinically relevant bleeding".

  • Percentage of Participants Who Required the Initiation of Curative Anticoagulant or Thrombolytic Treatment After VTE Assessment [ Time Frame: From randomization up to 10 days after surgery 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 answer to the question "was the subject treated for VTE?" asked after the diagnostic tests for suspected VTE and after the mandatory venography.


Other Outcome Measures:
  • Overview of deaths [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]
    All deaths were centrally and blindly reviewed by the CIAC and classified as fatal PE, fatal bleeding, cardiovascular death or other based on relevant documentation (e.g. autopsy report).

  • Platelets Count: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ 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: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA] [ Time Frame: From first study drug injection up to 3 days after last study drug injection ] [ Designated as safety issue: Yes ]

    Thresholds were defined as follows:

    • Alanine Aminotransferase [ALAT] >3 Upper Normal Limit [ULN];
    • Total Bilirubin [TB] >2 ULN;
    • ALAT >3 ULN and TB >2 ULN;

    Cases with ALAT >3 ULN and TB >2 ULN (not necessarily concomitant) were evaluated by a blinded independent adjudicator to determine if they met Hy's law criteria.



Enrollment: 1150
Study Start Date: July 2008
Study Completion Date: May 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Semuloparin

Semuloparin sodium 20 mg (10 mg if Severe Renal Impairment [SRI]) once daily for 7-10 days with an initial dose given 8 hours after surgery

To maintain the blind, placebo for Enoxaparin sodium:

  • 12 and 24 hours after surgery, then once daily if no SRI
  • 12 hours after surgery only if SRI
Drug: Semuloparin sodium

0.3 mL (0.2 mL if SRI) solution in ready-to-use 0.5 mL pre-filled syringe

Subcutaneous injection

Other Name: AVE5026
Drug: Placebo

0.3 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml prefilled syringe strictly identical in appearance but without active component

Subcutaneous injection

Active Comparator: Enoxaparin

Enoxaparin sodium 30 mg twice daily (20 mg once daily if Severe Renal Impairment [SRI]) for 7-10 days with an initial dose given 12 hours after surgery

Placebo for Semuloparin sodium 8 hours after surgery to maintain the blind

Drug: Enoxaparin

0.3 mL (0.2 mL if SRI) solution in ready-to-use 0.5 mL pre-filled syringe

Subcutaneous injection

Other Name: Lovenox®
Drug: Placebo

0.3 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml prefilled syringe strictly identical in appearance but without active component

Subcutaneous injection


Detailed Description:

Randomization had to take place just prior the first study drug injection (randomization ratio 1:1).

The total duration of observation per participant was 35-42 days from surgery broken down as follows:

  • 7 to 10-day double-blind treatment period;
  • 28 to 35-day follow-up period.

Mandatory bilateral venography of the lower limbs had to be performed 7 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:

- Knee replacement surgery or revision of at least one component of a knee prosthesis implanted ≥ 6 months prior to study entry.

Exclusion Criteria:

  • Any major orthopedic surgeries in the 3 months prior to study;
  • Deep vein thrombosis or pulmonary embolism within the last 12 months, or known post-phlebitic syndrome;
  • Any contraindications to the performance of venography;
  • High risk of bleeding;
  • Know allergy to heparin, or enoxaparin, or pork products;
  • End stage renal disease or patient on dialysis.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00718224

  Hide Study Locations
Locations
United States, New Jersey
Sanofi-Aventis Administrative Office
Bridgewater, New Jersey, United States, 08807
Argentina
Sanofi-Aventis Administrative Office
Buenos Aires, Argentina
Australia, New South Wales
sanofi-aventis Australia & New Zealand administrative office
Macquarie Park, New South Wales, Australia
Belarus
Sanofi-Aventis Administrative Office
Minsk, Belarus
Canada
Sanofi-Aventis Administrative Office
Laval, Canada
Colombia
Sanofi-Aventis Administrative Office
Santafe de Bogota, Colombia
Czech Republic
Sanofi-Aventis Administrative Office
Praha, Czech Republic
Denmark
Sanofi-Aventis Administrative Office
Horsholm, Denmark
Estonia
Sanofi-Aventis Administrative Office
Tallinn, Estonia
Greece
Sanofi-Aventis Administrative Office
Athens, Greece
Lithuania
Sanofi-Aventis Administrative Office
Vilnius, Lithuania
Mexico
Sanofi-Aventis Administrative Office
Mexico, Mexico
Poland
Sanofi-Aventis Administrative Office
Warszawa, Poland
Romania
Sanofi-Aventis Administrative Office
Bucuresti, Romania
Russian Federation
Sanofi-Aventis Administrative Office
Moscow, Russian Federation
South Africa
Sanofi-Aventis Administrative Office
Midrand, South Africa
Ukraine
Sanofi-Aventis Administrative Office
Kiev, Ukraine
Sponsors and Collaborators
Sanofi
Investigators
Principal Investigator: Michael R. LASSEN, MD Horsholm Hospital, Horsholm, Denmark
Study Chair: Alexander G. TURPIE, MD McMaster University
  More Information

Publications:
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00718224     History of Changes
Other Study ID Numbers: EFC10571, 2007-007946-37
Study First Received: July 17, 2008
Last Updated: January 14, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Sanofi:
Knee surgery
VTE prevention

Additional relevant MeSH terms:
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism and Thrombosis
Thrombosis
Vascular Diseases

ClinicalTrials.gov processed this record on October 23, 2014