E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Venous Thromboembolism Prophylaxis |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of blood clot within a vein |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 demonstrate the non-inferiority of rivaroxaban 10 mg versus Enoxaparin 4000 IU with respect to the occurrence of major venous thromboembolism (VTE) up to the end of treatment (e.g. removal of the plaster cast or brace). The study is powered to further demonstrate the superiority of Rivaroxaban 10mg once daily versus standard of care with respect to the occurrence of the primary endpoint. This superiority analysis will be performed only if the primary objective of non-inferiority is met. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate the safety of rivaroxaban compared to enoxaparin in terms of: 1- Major bleeding 2- Clinically relevant non-major bleeding 3- Thrombocytopenia 4- All cause mortality during treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated informed consent form, 2. Age ≥ 18 years, 3. Hospitalised for non-major orthopaedic surgery of the lower limbs and requiring thromboprophylaxis according to the investigator’s judgement on VTE risk such Achilles’ repair, knee (including unicompartmental knee prosthesis), tibial plateau, femur (non femoral head), tibial and ankle fractures and tibial osteotomy, tibial transposition, arthrodesis of leg articulation, ligament repair of the knee with a planned immobilisation or partial weight-bearing for more than 2 weeks, ligament repair of the ankle or any elective orthopaedic limb surgery requiring thromboprophylaxis, 4. An intended duration of treatment for at least 2 weeks.
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E.4 | Principal exclusion criteria |
1. Major orthopaedic surgery: Hip and Knee replacement, femoral neck and trochanteric fractures, spine surgery, 2. Polytrauma (each lesion being individually life-threatening) or any life-threatening lesions, 3. Low risk surgery without patient VTE risk: Forefoot surgery (i.e. Hallux Valgus), material removal, Meniscectomy, Knee arthroscopy (except for ligament repair), Meniscal suture, Diagnostic arthroscopy 4. Time between hospitalisation and surgery greater than 48 hours, 5. More than one injection of LMWH since the end of surgery, 6. More than two injections of LMWH before surgery, 7. Women of childbearing potential not using a reliable contraceptive method throughout the study period. The reliable contraceptive methods are defined as the following: hormonal contraception (per os / implant / transdermal / injectable), intrauterine device (with or without hormone), condom (male or female), tubal ligation, partner’s vasectomy, sexual abstinence, 8. Women pregnant or breast-feeding during the study period, 9. Body weight less than 50 kg (to avoid bleeding over risk) or over 120 kg, 10. Concomitant Treatment with VKA therapy or DOAs, 11. Concomitant treatment with clopidogrel, prasugrel and ticagrelor, 12. Concomitant Use of strong inhibitors of both CYP3A4 and P-gp, i.e. all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, 13. Platelet count < 100 Giga/L, 14. Documented history of acquired or inherited bleeding disorder (e.g., von Willebrand's disease), 15. Severe renal failure with calculated creatinine clearance (Cockcroft Formula) < 30 mL/min, 16. Severe hepatic insufficiency with prothrombin time < 60% or liver impairment associated with coagulation disorders, 17. History of heparin induced thrombocytopenia, 18. Any other current significant medical condition that might interfere with treatment evaluation according to the investigator’s judgement, 19. Known hypersensitivity or other severe reaction to any component of the investigational medicinal product(s), 20. Participation in another clinical study involving an investigational medicinal product within 30 days prior to inclusion or concomitantly with this study, 21. Active bleeding or contraindication to anticoagulant therapy, 22. Chronic alcoholic intoxication (cirrhotic patient), 23. Anticipated poor compliance of subject with study procedures.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome, major VTE, is the composite of proximal Deep Venous Thrombosis (DVT) (asymptomatic and symptomatic), symptomatic events (distal and proximal DVT, Pulmonary Embolism) and VTE related deaths up to the end of the treatment period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
up to the end of the treatment period |
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E.5.2 | Secondary end point(s) |
1- Major bleeding. Major bleeding is defined as a bleeding event that meets at least one of the following criteria [5]: • fatal bleeding; • critical bleeding (intracranial, intraocular, intraspinal, pericardial, retroperitoneal); • clinically overt bleeding (at surgical or extrasurgical site) associated with a decrease in the haemoglobin level of more than 2 g/dL (20 g/l; 1.24 mmol/L) compared with the pre-randomization level; • clinically overt bleeding (at surgical or extrasurgical site) leading to transfusion of two or more units of whole blood or packed cells; • bleeding located at the surgical site and leading to re-operation or to any unusual medical intervention or procedure for relief (e.g. draining or puncture of an haematoma at the surgical site, transfer to an ICU or emergency room). 2- Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding and corresponds to any bleeding necessitating medical intervention or a specific, unscheduled consultation or treatment discontinuation, or resulting in a deterioration of the subject’s quality of life. Some examples of clinically significant bleeding are given below: • Epistaxis that lasts more than five minutes or recurrent or necessitates packing, • Spontaneous macroscopic haematuria or haematuria lasting more than 24 hours after instrumentation, • Gastrointestinal haemorrhage (melena or rectorrhagia), • Haemoptysis, • Subcutaneous haematoma > 100 cm². 3- Overt thrombocytopenia: platelet count <100 giga/L or fall ≥ 50% of the platelet count as compared with the first post-operative count which will be done as local lab for all centres. During the course of the study, platelet count monitoring will be done as per country recommendation and in case of bleedings and recurrent VTE. 4- All cause mortality during treatment All suspected VTEs, deaths, as well as all episodes of bleeding will be evaluated by a central, blinded, independent adjudication committee (ICAC). Adjudication results will be the basis for the final analyses.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
up to the end of the 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 | 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.8.2.4 | 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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 177 |
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 | No |
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 |
Canada |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Poland |
Spain |
Tunisia |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |