E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of venous thromboembolism (VTE) in patients undergoing high VTE-risk knee surgery |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of venous thromboembolism (VTE) in patients undergoing high VTE-risk knee surgery |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049909 |
E.1.2 | Term | Venous thromboembolism prophylaxis |
E.1.2 | System Organ Class | 100000004865 |
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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 |
To prove the non-inferiority of the test IMP to the reference IMP regarding the incidence of patients with any bleeding events until 24 hours after trial therapy discontinuation. |
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E.2.2 | Secondary objectives of the trial |
To compare the test IMP to the reference IMP regarding: 1. Major bleeding events; 2. Clinically-relevant non-major bleeding events; 3. Other bleeding events; 4. Incidence of proximal DVT (asymptomatic and symptomatic); 5. Incidence of distal DVT (symptomatic); 6. Incidence of symptomatic non-fatal PE; 7. VTE-related death; 8. Composite of proximal asymptomatic and symptomatic DVT, distal symptomatic DVT, symptomatic non-fatal PE and VTE-related death; 9. Any adverse events (AE), including brain stroke, myocardial infarction, unstable angina, cardiovascular death; with selection of those related to IMPs; 10. Treatment discontinuation rate due to adverse events; 11. Death from all causes; 12. Incidence of immune-mediated heparin-induced thrombocytopenia (HIT type II) and/or thromboembolism (HITT). Other parameters related to surgery (e.g. peri- and post-operative blood loss, requirement for blood transfusion) will be recorded.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Caucasian male or female patients scheduled to undergo elective, unilateral major knee surgery, including patients requiring a revision of at least one component of a previously implanted total-knee prosthesis, eligible for 14 days prophylaxis against VTE with enoxaparin; 2. 18 years of age or older; 3. Body weight > 45 kg in females and > 57 kg in males; 4. Patients capable of understanding and following the study procedures, who will give their Informed Consent in a written form before any study qualification procedures begin.
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E.4 | Principal exclusion criteria |
1. Contraindications to surgery or any medical procedure required by the type of surgery (e.g. type of anaesthesia, urinary catherization if required etc.); 2. Contraindications to enoxaparin treatment in accordance with Clexane SmPC: • acute bacterial endocarditis; • active major bleeding; • conditions with a high risk of uncontrolled haemorrhage (e.g. recent haemorrhagic stroke); • active gastric or duodenal ulceration; • hypersensitivity to either enoxaparin sodium, heparin or its derivatives including other low molecular weight heparins; 3. History of immune-mediated heparin-induced thrombocytopenia (HIT type II) and/or thromboembolism (HITT); 4. Known any bleeding diathesis; 5. Known inherited thrombophilic disorder such as the factor V Leiden or prothrombin gene mutations or deficiencies of antithrombin, protein C, or protein S; 6. Abnormal results of blood coagulation tests (activated partial thromboplastin time (aPTT), prothrombin time (PT), International Normalized Ratio (INR)); 7. Anaemia (HGB < 12 g/dL in females and < 13.0 g/dL in males); 8. Thrombocytopenia (PLT < 150 000/mm3), also if in history; 9. Thrombocytosis (PLT > 400 000/mm3), also if in history; 10. History of intracerebral, intraocular, gastrointestinal or urogenital bleeding, or active gastric or duodenal ulceration, within 6 months prior to randomization; 11. History of major surgery (invasive medical procedures involving tissues incision, requiring general or intrathecal anesthesia, access into the cavities of the body, associated with significant risk of major bleeding or in which the life of a patient is at stake, e.g. cardiac surgery, neurosurgery, ophthalmic surgery, abdominal surgery) within 3 months prior to randomization; 12. History of major trauma (defined as tissue, organ or large area of the body injury due to the action of mechanical, thermal, chemical or electrical factor etc.) within 3 months prior to randomization; 13. History of any thrombolytic or fibrynolysis inhibitor or anticoagulant use (except for heparins) within 4 weeks prior to randomization; 14. History of any heparin use within 100 days prior to randomization; 15. History of any antiplatelet use within 5 days prior to randomization; 16. Uncontrolled hypertension defined as systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening or at any time within 3 months prior to randomization; 17. Hyperkalemia; 18. History of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, cerebrovascular accident (CVA), or transient ischemic attack (TIA), within 6 months prior to randomization; 19. Severe cardiac failure (NYHA III-IV); 20. Unstable angina pectoris; 21. Known liver disease with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than three times the upper limit of the normal range; 22. Known renal disease (calculated creatinine clearance < 30 mL/min) or patients on dialysis; 23. Any suspected urinary tract infection; 24. Active oral cavity infections; 25. History of malignant neoplastic disease that has not been in remission for at least 5 years at screening; 26. Anticipated requirement for the use of pneumatic compression post-operatively or for continued (> 14 days) anticoagulation; 27. Severe peripheral vascular disease with ulceration or amputation; 28. Any confirmed or suspected acute hepatitis; 29. Pregnancy or lactation period in females; 30. Severe subjects who are known or suspected to be drug dependent, including those drinking more than 28 g alcohol per day; 31. Participation in another clinical trial within 12 weeks prior to randomization; 32. Severe physical or mental concomitant diseases that might hamper the realization of the trial according to the protocol or the evaluation of efficacy and safety; 33. Any acute or chronic medical condition or treatment that, in the opinion of the investigator, would render treatment with enoxaparin unsafe, interfere with the evaluation of responses, or render the subject unable or meet the requirements of any point of the protocol; 34. Taking any medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including e.g. salicylates of systemic action, non-steroidal anti-inflammatory drugs, corticosteroids of systemic action, anti-aggregating products and all other substances, which will be considered as important in the investigator’s opinion.; 35. Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope, and possible consequences of the study; 36. Unreliability or lack of cooperation; 37. Lack of possibility to attend the visits required by protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of patients with any bleeding events until 24 hours after trial therapy discontinuation. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
On day 15-16 of the study (after the 14-day treatment period) |
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E.5.2 | Secondary end point(s) |
To compare the test IMP to the reference IMP regarding: 1. Major bleeding events; 2. Clinically-relevant non-major bleeding events; 3. Other bleeding events; 4. Incidence of proximal DVT (asymptomatic and symptomatic); 5. Incidence of distal DVT (symptomatic); 6. Incidence of symptomatic non-fatal PE; 7. VTE-related death; 8. Composite of proximal asymptomatic and symptomatic DVT, distal symptomatic DVT, symptomatic non-fatal PE and VTE-related death; 9. Any adverse events (AE), including brain stroke, myocardial infarction, unstable angina, cardiovascular death; with selection of those related to IMPs; 10. Treatment discontinuation rate due to adverse events; 11. Death from all causes; 12. Incidence of immune-mediated heparin-induced thrombocytopenia (HIT type II) and/or thromboembolism (HITT). Other parameters related to surgery (e.g. peri- and post-operative blood loss, requirement for blood transfusion) will be recorded. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
On day 15-16 of the study (after the 14-day treatment period) |
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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 | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 15 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Last Visit Last Subject (LVLS) |
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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 | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |