Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban (CASTA-DIVA)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Neoplasm; Venous Thromboembolism	Drug: rivaroxaban; Drug: Low-molecular-weight heparin	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	200 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Single (Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Efficacy and Safety of Oral Rivaroxaban for the Treatment of Venous Thromboembolism in Patients With Active Cancer. A Pilot Study.
Study Start Date :	September 2016
Estimated Primary Completion Date :	March 2018
Estimated Study Completion Date :	March 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Low-molecular-weight heparin; dalteparin, 200 IU/kg subcutaneously once daily for one month followed by 150 IU/kg subcutaneously once daily for 2 months	Drug: Low-molecular-weight heparin; dalteparin, 200 IU/kg OD for 4 weeks followed by 150 IU/kg OD for 8 weeks; Other Name: dalteparin
Experimental: Rivaroxaban; rivaroxaban, orally, 15 mg twice daily for 3 weeks followed by 20 mg once daily for 9 weeks	Drug: rivaroxaban; rivaroxaban, 15 mg BD (Bis in die) for 3 weeks followed by 20mg OD (Omni die) for 9 weeks; Other Name: xarelto

Outcome Measures

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Primary Outcome Measures :

1. Symptomatic DVT [ Time Frame: 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)
2. Symptomatic PE [ Time Frame: 3 months ]
   Recurrent VTE during the 3-month treatment period including symptomatic PE
3. Unsuspected PE and DVT [ Time Frame: 3 months ]
   Recurrent VTE during the 3-month treatment period including clinically unsuspected PE and DVT discovered incidentally
4. Worsening of pulmonary vascular or venous obstruction [ Time Frame: 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

Secondary Outcome Measures :

1. Major and clinically significant bleedings during the 3-month treatment period [ Time Frame: 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.
2. Symptomatic recurrences of PE or DVT of the legs [ Time Frame: 3 months ]
   excluding visceral thrombosis, upper extremity deep vein thrombosis and clinically unsuspected PE and DVT diagnosed incidentally
3. Major and non-major clinically significant bleedings at day 90 [ Time Frame: 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.
4. Mortality [ Time Frame: 3 months ]

Other Outcome Measures:

1. Rivaroxaban plasma concentrations [ Time Frame: 3 months ]
   Area under the plasma concentration versus time curve (AUC) determined using a liquid chromatography-tandem mass spectrometry method

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Guy Meyer, MD		guy.meyer@aphp.fr
Contact: Christine Lanau		christine.lanau@aphp.fr

Locations

France
CHU Amiens - Medecine vasculaire (003)	Recruiting
Amiens, France
Contact: Marie-Antoinette SEVESTRE sevestre.marie-antoinette@chu-amiens.fr
CHU Angers - Medecin Interne (002)	Recruiting
Angers, France
Contact: Pierre Marie ROY pmroy@chu-angers.fr
Hopital Saint Andre - Medecine vasculaire (015)	Recruiting
Bordeaux, France
Contact: Joël CONSTANS joel.constans@chu-bordeaux.fr
CHU Brest - Departement de medecin interne et pneumologie (008)	Recruiting
Brest, France
Contact: Aurelien DELLUC aurelien.delluc@chu-brest.fr
CHU Le Bocage - Medecine interne 1 (014)	Recruiting
Dijon, France
Contact: Nicolas FALVO nicolas.falvo@chu-dijon.fr
CHU Grenoble - Medecine vasculaire (007)	Recruiting
Grenoble, France
Contact: Gilles PERNOD gpernod@chu-grenoble.fr
Bicetre - Service de Pneumologie et de soins intensifs (018)	Withdrawn
Le Kremlin Bicetre, France
Centre hospitalier Lyon Sud - Medecine interne (011)	Recruiting
Lyon, France
Contact: Claire GRANGE claire.grange@chu-lyon.fr
Hopital Saint Eloi - Service de medecine Interne et Maladies Vasculaire (004)	Withdrawn
Montpellier, France
CHRU de Nîmes - Pneumologie (012)	Recruiting
Nîmes, France
Contact: Alain PROUST alain.proust@chu-nimes.fr
HEGP - Pneumologie et soins intensifs (001)	Recruiting
Paris, France, 75015
Contact: Guy MEYER guy.meyer@aphp.fr
Cochin - Medecine interne (017)	Withdrawn
Paris, France
Institut Curie - Soins de support en Cancerologie (020)	Recruiting
Paris, France
Contact: Alexis BRUNOD alexis.burnod@curie.fr
Centre hospitalier de Pau - Service de Pneumologie (016)	Withdrawn
Pau, France
CHU Saint Etienne - Medecin vasculaire et therapeutique (006)	Recruiting
Saint Etienne, France
Contact: Laurent BERTOLETTI laurent.bertoletti@gmail.com
Hopital Saine Musse - Service de Medecine Vasculaire (010)	Recruiting
Toulon, France
Contact: Antoine ELIAS antoine.elias@free.fr
CHU Rangueil - Medecin Vasculaire (019)	Recruiting
Toulouse, France
Contact: Alessandra BURA bura-riviere@chu-toulouse.fr

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Bayer

Investigators

Principal Investigator:	Guy Meyer, MD	APHP - HEGP

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT02746185 History of Changes
Other Study ID Numbers:	P141204
First Posted:	April 21, 2016
Last Update Posted:	August 29, 2017
Last Verified:	August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Keywords provided by Assistance Publique - Hôpitaux de Paris:

cancer; venous thromboembolism; low-molecular weight heparin; rivaroxaban

Additional relevant MeSH terms:

Thromboembolism; Venous Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Calcium heparin; Heparin; Rivaroxaban; Heparin, Low-Molecular-Weight; Dalteparin	Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors