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

• 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.

• Composite of proximal deep vein thrombosis, symptomatic distal deep vein thrombosis, non fatal pulmonary embolism, all cause deaths [ Time Frame: From randomization up to an event or mandatory venography, whichever comes first ] [ Designated as safety issue: No ]
• Bleeding, transfusions, hemoglobin, platelet count, liver and renal laboratory tests [ Time Frame: Study period ] [ Designated as safety issue: Yes ]

• 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.

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.

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.

• 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: 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

• 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
  Interventions:

  • Drug: Semuloparin sodium
  • Drug: Placebo
• 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

  Interventions:

  • Drug: Enoxaparin
  • Drug: Placebo

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.