Clinical trial NCT02746185: Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban
Official title: Efficacy and Safety of Oral Rivaroxaban for the Treatment of Venous Thromboembolism in Patients With Active Cancer. A Pilot Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasm
Venous Thromboembolism
Keywords: cancer
venous thromboembolism
low-molecular weight heparin
rivaroxaban
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2016-04-21
Enrollment: 159
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Symptomatic DVT
timeFrame: 3 months
measure: Symptomatic PE
timeFrame: 3 months
measure: Unsuspected PE and DVT
timeFrame: 3 months
measure: Worsening of pulmonary vascular or venous obstruction
timeFrame: 3 months
Secondary outcomes:
measure: Major and clinically significant bleedings during the 3-month treatment period
timeFrame: 3 months
measure: Symptomatic recurrences of PE or DVT of the legs
timeFrame: 3 months
measure: Major and non-major clinically significant bleedings at day 90
timeFrame: 3 months
measure: Mortality
timeFrame: 3 months
Other outcomes:
measure: Rivaroxaban plasma concentrations
timeFrame: 3 months
Locations:
city: Amiens
country: France
facility: CHU Amiens - Medecine vasculaire (003)
city: Angers
country: France
facility: CHU Angers - Medecin Interne (002)
city: Arras
country: France
facility: Espace Artois Santé
city: Bordeaux
country: France
facility: Hopital Saint Andre - Medecine vasculaire (015)
city: Brest
country: France
facility: CHU Brest - Departement de medecin interne et pneumologie (008)
city: Dijon
country: France
facility: CHU Le Bocage - Medecine interne 1 (014)
city: Grenoble
country: France
facility: CHU Grenoble - Medecine vasculaire (007)
city: La Roche-sur-Yon
country: France
facility: CH Départemental La Roche sur Yon
city: Lyon
country: France
facility: Centre hospitalier Lyon Sud - Medecine interne (011)
city: Nîmes
country: France
facility: CHRU de Nîmes - Pneumologie (012)
city: Paris
country: France
facility: HEGP - Pneumologie et soins intensifs (001)
city: Paris
country: France
facility: Institut Curie - Soins de support en Cancerologie (020)
city: Saint Etienne
country: France
facility: CHU Saint Etienne - Medecin vasculaire et therapeutique (006)
city: Toulon
country: France
facility: Hopital Saine Musse - Service de Medecine Vasculaire (010)
city: Toulouse
country: France
facility: CHU Rangueil - Medecin Vasculaire (019)
Study officials:
affiliation: APHP - HEGP
name: Guy Meyer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Planquette B, Bertoletti L, Charles-Nelson A, Laporte S, Grange C, Mahe I, Pernod G, Elias A, Couturaud F, Falvo N, Sevestre MA, Ray V, Burnod A, Brebion N, Roy PM, Timar-David M, Aquilanti S, Constans J, Bura-Riviere A, Brisot D, Chatellier G, Sanchez O, Meyer G, Girard P, Mismetti P; CASTA DIVA Trial Investigators. Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial. Chest. 2022 Mar;161(3):781-790. doi: 10.1016/j.chest.2021.09.037. Epub 2021 Oct 8.
citation: Riaz IB, Fuentes HE, Naqvi SAA, He H, Sipra QR, Tafur AJ, Padranos L, Wysokinski WE, Marshall AL, Vandvik PO, Montori V, Bryce AH, Liu H, Badgett RG, Murad MH, McBane RD 2nd. Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis. Mayo Clin Proc. 2022 Feb;97(2):308-324. doi: 10.1016/j.mayocp.2020.10.041. Epub 2021 Jun 22.