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

Primary Purpose

Neoplasm, Venous Thromboembolism

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
rivaroxaban
Low-molecular-weight heparin
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neoplasm focused on measuring cancer, venous thromboembolism, low-molecular weight heparin, rivaroxaban

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • CHU Amiens - Medecine vasculaire (003)
  • CHU Angers - Medecin Interne (002)
  • Espace Artois Santé
  • Hopital Saint Andre - Medecine vasculaire (015)
  • CHU Brest - Departement de medecin interne et pneumologie (008)
  • CHU Le Bocage - Medecine interne 1 (014)
  • CHU Grenoble - Medecine vasculaire (007)
  • CH Départemental La Roche sur Yon
  • Centre hospitalier Lyon Sud - Medecine interne (011)
  • CHRU de Nîmes - Pneumologie (012)
  • HEGP - Pneumologie et soins intensifs (001)
  • Institut Curie - Soins de support en Cancerologie (020)
  • CHU Saint Etienne - Medecin vasculaire et therapeutique (006)
  • Hopital Saine Musse - Service de Medecine Vasculaire (010)
  • CHU Rangueil - Medecin Vasculaire (019)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Low-molecular-weight heparin

Rivaroxaban

Arm Description

dalteparin, 200 IU/kg subcutaneously once daily for one month followed by 150 IU/kg subcutaneously once daily for 2 months

rivaroxaban, orally, 15 mg twice daily for 3 weeks followed by 20 mg once daily for 9 weeks

Outcomes

Primary Outcome Measures

Symptomatic DVT
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
Recurrent VTE during the 3-month treatment period including symptomatic PE
Unsuspected PE and DVT
Recurrent VTE during the 3-month treatment period including clinically unsuspected PE and DVT discovered incidentally
Worsening of pulmonary vascular or venous obstruction
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

Major and clinically significant bleedings during the 3-month treatment period
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
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
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.
Mortality

Full Information

First Posted
December 15, 2015
Last Updated
August 10, 2018
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT02746185
Brief Title
Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban
Acronym
CASTA-DIVA
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

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
April 25, 2018 (Actual)
Study Completion Date
April 25, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Bayer

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplasm, Venous Thromboembolism
Keywords
cancer, venous thromboembolism, low-molecular weight heparin, rivaroxaban

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
159 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low-molecular-weight heparin
Arm Type
Active Comparator
Arm Description
dalteparin, 200 IU/kg subcutaneously once daily for one month followed by 150 IU/kg subcutaneously once daily for 2 months
Arm Title
Rivaroxaban
Arm Type
Experimental
Arm Description
rivaroxaban, orally, 15 mg twice daily for 3 weeks followed by 20 mg once daily for 9 weeks
Intervention Type
Drug
Intervention Name(s)
rivaroxaban
Other Intervention Name(s)
xarelto
Intervention Description
rivaroxaban, 15 mg BD (Bis in die) for 3 weeks followed by 20mg OD (Omni die) for 9 weeks
Intervention Type
Drug
Intervention Name(s)
Low-molecular-weight heparin
Other Intervention Name(s)
dalteparin
Intervention Description
dalteparin, 200 IU/kg OD for 4 weeks followed by 150 IU/kg OD for 8 weeks
Primary Outcome Measure Information:
Title
Symptomatic DVT
Description
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)
Time Frame
3 months
Title
Symptomatic PE
Description
Recurrent VTE during the 3-month treatment period including symptomatic PE
Time Frame
3 months
Title
Unsuspected PE and DVT
Description
Recurrent VTE during the 3-month treatment period including clinically unsuspected PE and DVT discovered incidentally
Time Frame
3 months
Title
Worsening of pulmonary vascular or venous obstruction
Description
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
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Major and clinically significant bleedings during the 3-month treatment period
Description
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.
Time Frame
3 months
Title
Symptomatic recurrences of PE or DVT of the legs
Description
excluding visceral thrombosis, upper extremity deep vein thrombosis and clinically unsuspected PE and DVT diagnosed incidentally
Time Frame
3 months
Title
Major and non-major clinically significant bleedings at day 90
Description
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.
Time Frame
3 months
Title
Mortality
Time Frame
3 months
Other Pre-specified Outcome Measures:
Title
Rivaroxaban plasma concentrations
Description
Area under the plasma concentration versus time curve (AUC) determined using a liquid chromatography-tandem mass spectrometry method
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guy Meyer, MD
Organizational Affiliation
APHP - HEGP
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Amiens - Medecine vasculaire (003)
City
Amiens
Country
France
Facility Name
CHU Angers - Medecin Interne (002)
City
Angers
Country
France
Facility Name
Espace Artois Santé
City
Arras
Country
France
Facility Name
Hopital Saint Andre - Medecine vasculaire (015)
City
Bordeaux
Country
France
Facility Name
CHU Brest - Departement de medecin interne et pneumologie (008)
City
Brest
Country
France
Facility Name
CHU Le Bocage - Medecine interne 1 (014)
City
Dijon
Country
France
Facility Name
CHU Grenoble - Medecine vasculaire (007)
City
Grenoble
Country
France
Facility Name
CH Départemental La Roche sur Yon
City
La Roche-sur-Yon
Country
France
Facility Name
Centre hospitalier Lyon Sud - Medecine interne (011)
City
Lyon
Country
France
Facility Name
CHRU de Nîmes - Pneumologie (012)
City
Nîmes
Country
France
Facility Name
HEGP - Pneumologie et soins intensifs (001)
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Institut Curie - Soins de support en Cancerologie (020)
City
Paris
Country
France
Facility Name
CHU Saint Etienne - Medecin vasculaire et therapeutique (006)
City
Saint Etienne
Country
France
Facility Name
Hopital Saine Musse - Service de Medecine Vasculaire (010)
City
Toulon
Country
France
Facility Name
CHU Rangueil - Medecin Vasculaire (019)
City
Toulouse
Country
France

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34627853
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.
Results Reference
derived
PubMed Identifier
34172290
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.
Results Reference
derived

Learn more about this trial

Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban

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