Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Thromboembolism in Patients Undergoing Elective Knee Replacement Surgery (SAVE-KNEE)
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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 |
- 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.
- 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.
- 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:
|
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 |
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
Show 17 Study Locations| 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 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