| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The subjects who will participate to this clinical trial are patients undergoing major abdominal surgery.
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049909 |
| E.1.2 | Term | Venous thromboembolism prophylaxis |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare the efficacy and safety of once daily (q.d.) subcutaneous (s.c.) injections of 20 mg AVE5026 (10 mg in SRI patients) with q.d. s.c. injections of 40 mg enoxaparin (20 mg in SRI patients) administered up to Day 7 – 10 for the prevention of venous thromboembolic events (VTE) in patients undergoing major abdominal surgery. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the safety of AVE5026 in patients undergoing major abdominal surgery, and to document AVE5026 exposures in this population. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients undergoing major surgery in the peritoneal and/or the retroperitoneal space and/or the pelvis minor (but not limited to the pelvis minor) for indications other than limited disease of the liver (including hepato-biliary system), the uterus or the prostate. Patients with an age of <60 years must have one of the following additional risk factors:
- History of VTE
- Obesity (BMI ≥30 kg/m 2 )
- Chronic Heart Failure
- Chronic Respiratory Failure
- Inflammatory Bowel Disease
- Cancer Surgery
• Signed informed consent
Note: Major surgery is defined as open surgery, under general anesthesia and lasting more than 45 minutes.
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| E.4 | Principal exclusion criteria |
Exclusion criteria related to study methodology:
1. Legal lower age limitations (country specific)
2. Life expectancy less than 3 months
3. Known pelvic venous obstruction
4. Any major orthopedic or general surgery in the 3 months prior to study start
5. Clinical signs or symptoms of DVT or PE within the last 12 months or known post phlebitic syndrome
6. Known sensitivity to iodine or contrast dyes, and any contra-indications to the performance of venography
7. Any treatment with other anti-thrombotic agents within 2 weeks prior to randomization or planned during the course of the study treatment period such as:
- Parenteral anticoagulants (unfractionated heparin [UFH, LMWH [eg enoxaparin, dalteparin, nadroparin...],
fondaparinux, bivalirudin, hirudin)
- Oral anticoagulants (eg vitamin K antagonists)
- GPIIb/IIIa antagonists: abciximab, eptifibatide, tirofiban
- Thrombolytic agents
Notes:
Chronic treatment with anti-platelet agents such as low-dose of aspirin (up to 325 mg/day) or clopidogrel or ticlopidine in patients with coronary artery disease is allowed.
To maintain the patency of a central venous catheter, saline flushing solutions are highly recommended. However, if it is local practice, flushing solutions with small amounts of heparin (max. 500 I.U.) are allowed.
8. Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, inability to receive daily injection (preferably by a Health Care Professional) after hospital discharge and unlikelihood of completing the study
9. Treatment with any investigational product or investigational device in the last 30 days or 5 half lives (whichever is longer) prior to randomization.
10. Any previous exposure to AVE5026 (e.g. participation in any previous AVE5026 clinical trial)
Note: A patient may not be randomized in the study more than once
Exclusion criteria related to enoxaparin:
11. Active major bleeding
12. Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium
13. Known hypersensitivity to enoxaparin sodium (e.g. pruritus, urticaria, anaphylactoid reactions)
14. Known hypersensitivity to heparin or pork products
15. Conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophtalmological surgery.
Exclusion criteria related to AVE5026:
16. End stage renal disease (estimated creatinine clearance <10 mL/min) or patient on dialysis
17. Pregnant or breast-feeding women
18. Women of childbearing potential not protected by highly effective contraceptive method of birth control as defined for contraception in the Informed Consent Form for the duration of the study and/or who are unwilling or unable to be tested for pregnancy.
Note: Pregnancy status should be checked by serum or urine pregnancy testing prior to exposure to the investigational product. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is a composite of any VTE confirmed by the blinded Central Independent Adjudication Committee (CIAC) and deaths from any cause reported during the efficacy evaluation period. The efficacy evaluation period lasts from the randomization up to the day of the mandatory bilateral venography, or up to Day 11, whichever comes first.
Mandatory bilateral venography of the lower limbs should be performed within one calendar day of last IP injection.
For all events requiring adjudication, an adjudication dossier containing relevant documentation such as all relevant films (venography or compression ultrasound [CUS] for DVT, ventilation/perfusion lung scan or pulmonary angiogram or spiral CT scan for PE, or autopsy report if available for death) will be provided to the Adjudication Committee.
Other endpoints
•Composite of the following endpoints recorded during the efficacy evaluation period: any proximal DVT, symptomatic distal DVT, non fatal PE, and all cause deaths. A symptomatic distal DVT will be defined as distal DVT confirmed by appropriate diagnostic tests and associated with consistent signs and symptoms of VTE. A systematic screening for signs and symptoms of VTE will be performed prior to any diagnostic tests for VTE.
•Initiation of curative anticoagulant or thrombolytic treatment by the investigator after local VTE assessment.
Safety parameters include major bleeding, clinically relevant non-major bleeding (adjudicated by a blinded Adjudication Committee), transfusions requirements, hemoglobin, platelets count, liver and renal laboratory data, serious and non-serious adverse events [(s)Aes] and deaths up to 3 calendar days after last IP injection and up to Day 42.
Pharmacokinetics:
Four blood samples per patient will be drawn in all patients from selected centers to document the AVE5026 exposures in this population.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 26 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 26 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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