Neoplasm, Venous Thromboembolism
Conditions
Keywords
cancer, venous thromboembolism, low-molecular weight heparin, rivaroxaban
Brief summary
The study will compare the efficacy and safety of oral rivaroxaban and subcutaneous dalteparin in patients with cancer associated thrombosis. It is designed as a non-inferiority open label randomized multicenter trial with blinded adjudication of outcome events.
Detailed description
Patients with active cancer and symptomatic pulmonary embolism, proximal deep vein thrombosis, iliac or caval thrombosis will be randomly assigned to receive either dalteparin using the CLOT regimen or to oral rivaroxaban using the conventional dosage given in the Einstein studies. Experimental and control treatments will be given for three months. The main outcome at three month will include all symptomatic and incidentally discovered venous thromboembolic events including pulmonary embolism (either objectively confirmed and death due to pulmonary embolism), lower limb and upper limb deep vein thrombosis, iliac, caval and visceral thrombosis and any worsening of vascular obstruction which will be collected systematically at inclusion and at day 90. The safety end-points will consist of the rate of major bleedings and the composite of major and non-major but clinically significant bleedings at day 90. All outcome events will be blindly adjudicated by a central independent adjudication committee.
Interventions
DRUGrivaroxaban
rivaroxaban, 15 mg BD (Bis in die) for 3 weeks followed by 20mg OD (Omni die) for 9 weeks
dalteparin, 200 IU/kg OD for 4 weeks followed by 150 IU/kg OD for 8 weeks
Sponsors
Bayer
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years * Social security affiliation * Written informed consent * Solid active cancer, high grade lymphoma or myeloma treated with Immunomodulatory drugs (IMiDs) (thalidomide or lenalidomide). Active cancer is defined as the presence of measurable disease or ongoing (or planned) chemotherapy, radiotherapy or targeted therapy at inclusion. * Histologically or cytologically proven cancer. * Symptomatic venous thromboembolism objectively confirmed diagnosed because of symptoms or discovered incidentally * High-risk of recurrent Venous thromboembolism (VTE) defined by a score of 0 or ≥ 1, using the following criteria: female sex (+1), lung cancer (+1), breast cancer (-1) non metastatic tumor (-2), previous VTE (+1).
Exclusion criteria
* Exclusive adjuvant hormonal treatment with no measurable residual disease * Sub-segmental isolated pulmonary embolism (PE) without associated proximal DVT * Isolated distal deep vein thrombosis (DVT) of the legs * Isolated upper-extremity DVT or superior vena cava thrombosis * Isolated visceral thrombosis * Platelet count \< 50 000 G/L * Active bleeding * Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C * Hemostatic defect with contraindication to anticoagulant treatment at therapeutic dosage * Vena cava filter at inclusion * Fibrinolytic therapy within 3 days preceding inclusion * Creatinine clearance \< 30 ml/min according to Cockcroft-Gault formula * Previous heparin-induced thrombocytopenia * Anticoagulant treatment at curative dosage for more than 3 days before inclusion * Pregnancy or lack of effective contraceptive treatment for women of childbearing age * Treatment with both strong CYP3A4 and P-glycoprotein (PgP) inhibitors: protease inhibitors for HIV disease, systemic ketoconazole * Treatment with a strong CYP3A4 inducer: rifampicin, carbamazepine, phenytoin. * Life expectancy \< 3 months * Eastern Cooperative Oncology Group (ECOG) level 3 or 4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Worsening of pulmonary vascular or venous obstruction | 3 months | Recurrent VTE during the 3-month treatment period including worsening of pulmonary vascular obstruction or venous obstruction on the systematic examinations performed at the end of the 3-month treatment period |
| Symptomatic DVT | 3 months | Recurrent VTE during the 3-month treatment period including all symptomatic DVT (lower limbs distal and proximal DVTs, iliac and caval thrombosis, visceral thrombosis and deep vein thrombosis of the arm) |
| Symptomatic PE | 3 months | Recurrent VTE during the 3-month treatment period including symptomatic PE |
| Unsuspected PE and DVT | 3 months | Recurrent VTE during the 3-month treatment period including clinically unsuspected PE and DVT discovered incidentally |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 3 months | — |
| Major and clinically significant bleedings during the 3-month treatment period | 3 months | Major bleeding is defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and includes any bleeding resulting in death; symptomatic bleeding in a critical organ including intracranial, intra spinal, intraocular, retroperitoneal, intra articular and pericardial bleeding and muscle bleeding resulting in compartment syndrome; symptomatic bleeding resulting in a decrease in the hemoglobin concentration of at least 2g/dL or resulting in the transfusion of at least two packs of blood red cells. |
| Symptomatic recurrences of PE or DVT of the legs | 3 months | excluding visceral thrombosis, upper extremity deep vein thrombosis and clinically unsuspected PE and DVT diagnosed incidentally |
| Major and non-major clinically significant bleedings at day 90 | 3 months | Clinically significant non-major bleedings are defined as any bleeding requiring hospitalization or a medical intervention including temporary withholding of anticoagulant treatment to stop bleeding. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rivaroxaban plasma concentrations | 3 months | Area under the plasma concentration versus time curve (AUC) determined using a liquid chromatography-tandem mass spectrometry method |
Countries
France
Outcome results
None listed