Evaluation of AVE5026 as Compared to Enoxaparin for the Prevention of Thromboembolism in Patients Undergoing Hip Fracture Surgery (SAVE-HIP2)

A Multinational, Multicenter, Randomized, Double-Blind Study Comparing the Efficacy and Safety of AVE5026 With Enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Hip Fracture Surgery

The primary objective was to compare the efficacy of once daily [q.d] subcutaneous [s.c.] injections of Semuloparin sodium (AVE5026) with q.d. s.c. injections of Enoxaparin for the prevention of Venous Thromboembolic Events [VTE] in patients undergoing hip fracture surgery.

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

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Semuloparin sodium; Drug: Enoxaparin sodium; Drug: Placebo

Detailed Description

Randomization had to take place just prior to 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 between 7 to 11 days after surgery.

• Study Type: Interventional
• Enrollment (Actual): 1003
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Belarus
  • Minsk, Belarus
    • Sanofi-Aventis Administrative Office
• Bulgaria
  • Sofia, Bulgaria
    • Sanofi-Aventis Administrative Office
• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• Chile
  • Santiago, Chile
    • Sanofi-Aventis Administrative Office
• China
  • Shangaï, China
    • Sanofi-Aventis Administrative Office
• Colombia
  • Bogota, Colombia
    • Sanofi-Aventis Administrative Office
• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• Greece
  • Athens, Greece
    • Sanofi-Aventis Administrative Office
• India
  • Mumbai, India
    • Sanofi-Aventis Administrative Office
• Italy
  • Milano, Italy
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Peru
  • Lima, Peru
    • Sanofi-Aventis Administrative Office
• Poland
  • Warszawa, Poland
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Romania
  • Bucuresti, Romania
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• South Africa
  • Midrand, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Turkey
  • Istanbul, Turkey
    • Sanofi-Aventis Administrative Office
• Ukraine
  • Kiev, Ukraine
    • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Standard surgery for fracture of the upper third of the femur including femoral head and neck.

Exclusion Criteria:

• Estimated time of injury/fracture > 24 hours before admission to hospital;
• Any major orthopedic surgery in the 3 months prior to study start;
• Multiple trauma affecting more than one organ system;
• Deep vein thrombosis or pulmonary embolism within the last 12 months or known post-phlebitic syndrome;
• High risk of bleeding;
• Known 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Placebo for Enoxaparin sodium prior to surgery according to local standard for Enoxaparin and 12 hours after surgery to maintain the blind	Drug: Semuloparin sodium; 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml pre-filled syringe Subcutaneous injection; Other Names: AVE5026; Drug: Placebo; 0.4 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 40 mg (20 mg if Severe Renal Impairment [SRI]) once daily for 7-10 days with an initial dose given prior to or 12 hours after surgery according to local standard for Enoxaparin sodium Placebo for Semuloparin sodium 8 hours after surgery to maintain the blind	Drug: Enoxaparin sodium; 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml pre-filled syringe Subcutaneous injection; Other Names: Lovenox®; Drug: Placebo; 0.4 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced Venous Thromboembolism Event [VTE] or All-cause Death	VTE included any Deep Vein Thrombosis [DVT] (proximal or distal, symptomatic or not) and non-fatal Pulmonary Embolism [PE] as confirmed by a Central Independent Adjudication Committee [CIAC] after review of mandatory bilateral venograms and diagnostic tests for VTE. All-cause deaths included fatal PE and deaths for other reason than PE.	From randomization up to 10 days after surgery or the day of mandatory venography, whichever came first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced "Major" VTE or All-cause Death	"major" VTE included any proximal DVT, symptomatic distal DVT and non-fatal PE as confirmed by the CIAC.	From randomization up to 10 days after surgery or the day of mandatory venography, whichever came first
Percentage of Participants Who Experienced Clinically Relevant Bleedings	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".	From first study drug injection up to 3 days after last study drug injection
Percentage of Participants Who Required the 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 answer to the question "was the subject treated for VTE?" asked after the diagnostic tests for suspected VTE and after the mandatory venography.	From randomization up to 10 days after surgery or the day of mandatory venography, whichever came first

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overview of deaths	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).	From first study drug injection up to 3 days after last study drug injection
Platelets Count: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA]	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.	From first study drug injection up to 3 days after last study drug injection
Liver Function: Percentage of Participants With Potentially Clinically Significant Abnormalities [PCSA]	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.	From first study drug injection up to 3 days after last study drug injection

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Principal Investigator: William D. Fisher, MD, Department of Orthopaedic Surgery, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada; Study Chair: Alexander G. Turpie, McMaster University

Publications and helpful links

General Publications

• Lassen MR, Fisher W, Mouret P, Agnelli G, George D, Kakkar A, Mismetti P, Turpie AG; SAVE Investigators. Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE. J Thromb Haemost. 2012 May;10(5):822-32. doi: 10.1111/j.1538-7836.2012.04701.x.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (ACTUAL): October 1, 2009
• Study Completion (ACTUAL): October 1, 2009

Study Registration Dates

• First Submitted: July 22, 2008
• First Submitted That Met QC Criteria: July 22, 2008
• First Posted (ESTIMATE): July 24, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): January 23, 2013
• Last Update Submitted That Met QC Criteria: January 14, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Hip fractures; Heparin Low-Molecular-Weight
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Fractures, Bone; Wounds and Injuries; Leg Injuries; Embolism and Thrombosis; Femoral Fractures; Hip Injuries; Hip Fractures; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium; Semuloparin
• Other Study ID Numbers: EFC10343; 2007-007945-11 (EUDRACT_NUMBER)