Evaluation of AVE5026 as Compared to Placebo for the Extended Prophylaxis of Venous Thromboembolism in Patients Having Undergone Hip Fracture Surgery (SAVE-HIP3)

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

The primary objective is to evaluate the efficacy of once daily (QD) subcutaneous (SC) injections of Semuloparin sodium (AVE5026) versus placebo for 3 additional weeks following an initial 7 to 10-day venous thromboprophylaxis with open-label AVE5026 in patients having undergone hip fracture surgery.

The secondary objective is to evaluate the safety of extended AVE5026 administration.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Open-label Semuloparin sodium; Drug: Semuloparin sodium; Drug: Placebo (for Semuloparin sodium)

Detailed Description

The total duration of observation per participant is 56-63 days from surgery broken down as follows:

• 7 to 10-day initial treatment period with open-label Semuloparin sodium;
• Randomization;
• 19 to 23-day double-blind treatment period with Semuloparin sodium or placebo;
• 30-day follow-up period.

Mandatory bilateral venography of the lower limbs is to be performed between 19 and 24 days after randomization.

• Study Type: Interventional
• Enrollment (Actual): 469
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Minsk, Belarus
    • 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
  • Santafe de Bogota, Colombia
    • Sanofi-Aventis Administrative Office
• Egypt
  • Cairo, Egypt
    • Sanofi-Aventis Administrative Office
• India
  • Mumbai, India
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Lithuania
  • Vilnius, Lithuania
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Peru
  • Lima, Peru
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• South Africa
  • Midrand, South Africa
    • 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:

• In the run-in phase:

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

• In the double-blind phase following the run-in phase:

  • Completion of the run-in phase without permanent treatment discontinuation

Exclusion Criteria:

• Any major orthopedic surgery within 3 months prior to enrolment;
• Deep vein thrombosis or pulmonary embolism within the last 12 months, or known post-phlebitic syndrome;
• High risk of bleeding;
• Known hypersensitivity to heparins;
• Any contraindication to the performance of venography;
• 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 Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semuloparin extension treatment; Extension treatment with Semuloparin sodium 20 mg (10 mg if SRI) for 19-23 days following initial treatment with open-label Semuloparin 20 mg (10 mg if SRI) for 7-10 days.	Drug: Open-label Semuloparin sodium; 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml pre-filled syringe Subcutaneous injection once daily with an initial dose given 8 hours after surgery; Other Names: AVE5026; Drug: Semuloparin sodium; 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml pre-filled syringe Subcutaneous injection once daily; Other Names: AVE5026
Placebo Comparator: Placebo extension treatment; Extension treatment with placebo (for Semuloparin sodium) for 19-23 days following initial treatment with open-label Semuloparin 20 mg (10 mg if SRI) for 7-10 days	Drug: Open-label Semuloparin sodium; 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml pre-filled syringe Subcutaneous injection once daily with an initial dose given 8 hours after surgery; Other Names: AVE5026; Drug: Placebo (for Semuloparin sodium); 0.4 mL (0.2 mL if SRI) solution in ready-to-use 0.5 ml prefilled syringe strictly identical in appearance containing the same volume but without active component Subcutaneous injection once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experience Venous Thromboembolism Events (VTE) or Death From Any Cause During the Extension Treatment Period	VTE include any Deep Vein Thrombosis (DVT) (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 suspected VTE. All-cause deaths include fatal PE and deaths for other reason than PE.	From randomization up to 24 days after randomization or the day of mandatory venography, whichever comes first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experience "Major" VTE or Death From Any Cause	"Major" VTE include any proximal DVT, symptomatic distal DVT and non-fatal PE as confirmed by the CIAC.	From randomization up to 24 days after randomization or the day of mandatory venography, whichever comes first
Percentage of Participants Who Experience Clinically Relevant Bleedings During the Extension Treatment Period	Bleedings are 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 health care professional); "Non-clinically relevant bleeding".	From 1st study drug injection in the extension treatment period up to 3 days after last study drug injection
Percentage of Participants Who Require the Initiation of Curative Anticoagulant or Thrombolytic Treatment After VTE Assessment During the Extension Treatment Period	Initiation of curative anticoagulant or thrombolytic treatment after VTE assessment is 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 24 days after randomization or the day of mandatory venography, whichever comes first

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overview of Reported Bleeding Adverse Event	Analysis periods are defined as follows: Initial treatment: time from the first study drug injection up to the first injection in the extension period or up to 3 days after the last injection if no extension treatment;; Extension treatment: time from first injection in the extension period up to 3 days after the last injection.	From 1st study drug injection up to 3 days after last study drug injection
Overview of Deaths	The same analysis periods as defined for the previous outcome measure are used. In addition deaths during the extension treatment period are 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 1st 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 pre-defined criteria based on literature review. Threshold for platelets count was defined as <100 Giga/L. The analysis periods as previously defined are used (see outcome measure 5).	From 1st study drug injection up to 3 days after last study drug injection
Liver Function: Percentage of Participants With Potentially Clinically Significant Abnormalities (PCSA)	Thresholds are defined as follows: Alanine Aminotransferase [ALT] >3 Upper Normal Limit [ULN];; Total Bilirubin [TB] >2 ULN;; ALT >3 ULN and TB >2 ULN; Cases with ALT >3 ULN and TB >2 ULN (not necessarily concomitant) are evaluated by a blinded independent adjudicator to determine if they met Hy's law criteria. The analysis periods as previously defined are used (see outcome measure 5).	From 1st study drug injection up to 3 days after last study drug injection

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Principal Investigator: William D. Fisher, MD, McGill University Health Centre, Montreal, Quebec, Canada; Study Chair: Alexander G. TURPIE, MD, HHS-General Hospital, Hamilton, Ontario, Canada

Publications and helpful links

General Publications

• Fisher WD, Agnelli G, George DJ, Kakkar AK, Lassen MR, Mismetti P, Mouret P, Turpie AG. Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study. Bone Joint J. 2013 Apr;95-B(4):459-66. doi: 10.1302/0301-620X.95B4.30730.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: July 1, 2008
• First Submitted That Met QC Criteria: July 1, 2008
• First Posted (Estimate): July 3, 2008

Study Record Updates

• Last Update Posted (Estimate): June 14, 2013
• Last Update Submitted That Met QC Criteria: June 6, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: primary prevention; orthopedic surgery; venous thromboprophylaxis
• 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; Heparin, Low-Molecular-Weight; Semuloparin
• Other Study ID Numbers: EFC10636; 2007-007947-28 (EudraCT Number)