A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism (VTE) Prophylaxis in Ambulatory Cancer Participants

Efficacy and Safety of Rivaroxaban Prophylaxis Compared With Placebo in Ambulatory Cancer Patients Initiating Systemic Cancer Therapy and at High Risk for Venous Thromboembolism

The purpose of this study is to demonstrate that rivaroxaban is superior to placebo for reducing the risk of the primary composite outcome as defined by objectively confirmed symptomatic lower extremity proximal deep vein thrombosis (DVT), asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal pulmonary embolism (PE), incidental PE, and venous thromboembolism (VTE)-related death in ambulatory adult participants with various cancer types receiving systemic cancer therapy who are at high risk of developing a VTE.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Placebo

Detailed Description

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, superiority study comparing the efficacy and safety of rivaroxaban with placebo for primary prophylaxis of venous thromboembolism (VTE) in ambulatory adult participants, with various cancer types who are scheduled to initiate systemic cancer therapy. The study consists of 3 Phases: Screening Phase (14 Days), double-blind treatment Phase (180 Days) and follow up Phase (30 Days). The duration of participation in the study for each participant is approximately 32 weeks.

• Study Type: Interventional
• Enrollment (Actual): 841
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Amberloup, Belgium
  • Bonheiden, Belgium
  • Brussel, Belgium
  • Bruxelles, Belgium
  • Edegem, Belgium
  • Laken (brussel), Belgium
  • Turnhout, Belgium
  • Wilrijk, Belgium
• Brazil
  • Barretos, Brazil
  • Caxias do Sul, Brazil
  • Curitiba, Brazil
  • Itajai, Brazil
  • Lajeado, Brazil
  • Londrina, Brazil
  • Mogi das Cruzes, Brazil
  • Porto Alegre, Brazil
  • Porto Alegre, Rs, Brazil
  • Rio de Janeiro, Brazil
  • Santo André, Brazil
  • Sao Jose do Rio Preto, Brazil
  • Sao Paulo, Brazil
  • Sorocaba, Brazil
  • São Paulo, Brazil
• Bulgaria
  • Plovdiv, Bulgaria
  • Plovdiv N/a, Bulgaria
  • Sofia, Bulgaria
• Canada
  • Quebec, Canada
  • Ontario
    • Toronto, Ontario, Canada
  • Quebec
    • Saint-Jerome, Quebec, Canada
• Czechia
  • Benesov Nad Cernou, Czechia
  • Brno, Czechia
  • Jindrichuv Hradec, Czechia
  • Kladno, Czechia
  • Liberec, Czechia
  • Novy Jicin, Czechia
  • Olomouc, Czechia
  • Pardubice, Czechia
  • Praha 4, Czechia
  • Praha 5, Czechia
  • Tabor, Czechia
• France
  • Angers, France
  • Angers Cedex 9, France
  • Avignon Cedex 9, France
  • Dijon Cedex, France
  • Hyers, France
  • Le Mans Cedex 2, France
  • Le Mans cedex 9, France
  • Paris, France
  • Rennes Cedex, France
  • Saint Herblain, France
  • Valenciennes, France
• Germany
  • Berlin, Germany
  • Brandenburg, Germany
  • Dortmund, Germany
  • Dresden, Germany
  • Esslingen, Germany
  • Gauting, Germany
  • Hamburg, Germany
  • Hannover, Germany
  • Herne, Germany
  • Kiel, Germany
  • Koeln, Germany
  • Leipzig, Germany
  • Luebeck, Germany
  • Magdeburg, Germany
  • Merseburg, Germany
  • Minden, Germany
  • München, Germany
  • Paderborn, Germany
  • Recklinghausen, Germany
  • Weiden, Germany
• Russian Federation
  • Arkhangelsk, Russian Federation
  • Chelyabinsk, Russian Federation
  • Kursk, Russian Federation
  • Moscow, Russian Federation
  • Novosibirsk, Russian Federation
  • Omsk, Russian Federation
  • Saint Petersburg, Russian Federation
  • St Petersburg, Russian Federation
  • Tomsk, Russian Federation
  • Yaroslavi, Russian Federation
• United Kingdom
  • Bournemouth, United Kingdom
  • Cheltenham, United Kingdom
  • Dundee, United Kingdom
  • London, United Kingdom
  • Manchester, United Kingdom
  • Plymouth, United Kingdom
  • Swindon, United Kingdom
• United States
  • Arizona
    • Phoenix, Arizona, United States
    • Tucson, Arizona, United States
  • Arkansas
    • Little Rock, Arkansas, United States
  • California
    • Los Angeles, California, United States
    • Martinez, California, United States
    • Santa Barbara, California, United States
    • Torrance, California, United States
    • Upland, California, United States
  • Colorado
    • Denver, Colorado, United States
  • Connecticut
    • Norwich, Connecticut, United States
  • Florida
    • Gainesville, Florida, United States
    • Miami, Florida, United States
    • Miami Shores, Florida, United States
    • New Port Richey, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Illinois
    • Evanston, Illinois, United States
    • Joliet, Illinois, United States
    • Peoria, Illinois, United States
    • Rockford, Illinois, United States
    • Skokie, Illinois, United States
    • Urbana, Illinois, United States
  • Indiana
    • Anderson, Indiana, United States
  • Iowa
    • Cedar Rapids, Iowa, United States
  • Maine
    • Brewer, Maine, United States
  • Maryland
    • Baltimore, Maryland, United States
    • Silver Spring, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Detroit, Michigan, United States
  • Minnesota
    • Rochester, Minnesota, United States
    • Saint Cloud, Minnesota, United States
  • Missouri
    • Kansas City, Missouri, United States
  • Nebraska
    • Grand Island, Nebraska, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • New Hampshire
    • Lebanon, New Hampshire, United States
  • New York
    • Albany, New York, United States
    • Bronx, New York, United States
    • East Syracuse, New York, United States
    • New York, New York, United States
    • Rochester, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
    • High Point, North Carolina, United States
  • Ohio
    • Cleveland, Ohio, United States
  • Oregon
    • Eugene, Oregon, United States
    • Portland, Oregon, United States
  • Pennsylvania
    • Erie, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
    • Greenville, South Carolina, United States
    • North Charleston, South Carolina, United States
  • South Dakota
    • Rapid City, South Dakota, United States
  • Tennessee
    • Nashville, Tennessee, United States
  • Texas
    • Abilene, Texas, United States
    • Austin, Texas, United States
    • Beaumont, Texas, United States
    • Bedford, Texas, United States
    • Dallas, Texas, United States
    • Denton, Texas, United States
    • Flower Mound, Texas, United States
    • Garland, Texas, United States
    • Houston, Texas, United States
    • Paris, Texas, United States
    • San Antonio, Texas, United States
    • Sugar Land, Texas, United States
    • Temple, Texas, United States
    • The Woodlands, Texas, United States
    • Tyler, Texas, United States
    • Waco, Texas, United States
  • Virginia
    • Roanoke, Virginia, United States
    • Winchester, Virginia, United States
  • Wisconsin
    • Green Bay, Wisconsin, United States
    • Weston, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have histologically confirmed solid malignancy including but not limited to: pancreas, lung, stomach, colon, rectum, bladder, breast, ovary, renal or lymphoma (hematologic), with locally advanced or metastatic disease
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Have a Khorana thromboembolic risk Score greater than or equal to (>=) 2
• Creatinine clearance (CrCl) >= 30 milliliter per minute (mL/min)
• Plan to initiate systemic cancer therapy within plus or minus (+-) 1 week of receiving the first dose of study drug with the intention of receiving systemic cancer therapy during the double-blind treatment period for an intended duration determined by the treating oncologist according to standard protocols of clinical care

Exclusion Criteria:

• Diagnosis of primary brain tumors
• Known history of brain metastases
• Bleeding diathesis, hemorrhagic lesions, active bleeding, and other conditions with a high risk for bleeding
• Hematologic malignancies with the exception of lymphoma
• Platelet count less than (<) 50,000/millimeter^3 (mm^3), Life expectancy of less than or equal to (<=) 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban; Participants will be administered rivaroxaban 10 milligram (mg) tablet orally once daily for 180 days.	Drug: Rivaroxaban; Rivaroxaban 10 milligram (mg) tablet will be administered orally once daily for 180 days.
Experimental: Placebo; Participants will be administered matching placebo tablet orally once daily for 180 days.	Drug: Placebo; Placebo tablet will be administered orally once daily for 180 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Time to First Occurrence of Primary Efficacy Endpoint (Composite and Components)	Percentage of participants with time to the first occurrence of primary efficacy endpoint (composite and components) was reported. The primary efficacy composite endpoint is time to first occurrence of objectively confirmed symptomatic and asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE, or VTE-related death as adjudicated by an independent blinded Clinical Endpoint Committee (CEC).	Up to Day 180
Percentage of Participants With Time to the First Occurrence of Major Bleeding Events as Defined by International Society of Thrombosis and Haemostasis (ISTH)	Major bleeding is defined as clinically overt bleeding that is associated with a reduction in hemoglobin of 2 gram per deciliter (g/dL) or more, or a transfusion of 2 or more units of packed red blood cells or whole blood, or occurrence at a critical site defined as intracranial, intra-spinal, intraocular, pericardial, intra-articular, intra-muscular with compartment syndrome, retroperitoneal, or fatal outcome.	From first dose of study drug to 2 days after the last dose of the study drug (up to 32 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Time to the First Occurrence of Symptomatic VTE Events or VTE-Related Deaths	Percentage of participants with time to first occurrence of the composite endpoint of symptomatic VTE events (symptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, or symptomatic non-fatal PE) or VTE related deaths as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With All-Cause Mortality	Percentage of participants with all-cause mortality as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported. Overall deaths occurred during observation period (defined by start to end date of the observation period [that is approximately 180 days] are reported here.	Up to Day 180
Percentage of Participants With Time to the First Occurrence of Fatal or Non-fatal Arterial Thromboembolic Events (ATE)	Percentage of participants with time to first occurrence of fatal/non-fatal ATE (a composite of occurrence of myocardial infarction (MI), stroke [ischemic infarction with or without hemorrhagic conversion or primary hemorrhagic events - intraparenchymal hemorrhage, subdural hematoma or epidural hematoma] or any other ATE recorded) event as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to the First Occurrence of Fatal or Non-fatal Visceral VTE	Percentage of participants with time to the first occurrence of fatal or non-fatal visceral VTE as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to the First Occurrence of Composite Efficacy Endpoint 1	Percentage of participants with time to first occurrence of composite efficacy endpoint 1 (composite of objectively confirmed symptomatic and asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, incidental PE or all-cause mortality) as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to First Occurrence of Composite Efficacy Endpoint 2	Percentage of participants with time to first occurrence of composite efficacy endpoint 2 (composite of objectively confirmed symptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE or VTE-related deaths) as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to First Occurrence of Composite Efficacy Endpoint 3	Percentage of participants with time to first occurrence of composite efficacy endpoint 3 (composite of objectively confirmed symptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, asymptomatic lower extremity proximal DVT, symptomatic non-fatal PE, incidental PE, VTE-related deaths, fatal/non-fatal ATE [MI, stroke {ischemic infarction with or without hemorrhagic conversion or primary hemorrhagic events - intraparenchymal hemorrhage, subdural hematoma or epidural hematoma} or any ATE] or fatal/non-fatal visceral VTE) as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to First Occurrence of Composite Efficacy Endpoint 4	Percentage of participants with time to first occurrence of composite efficacy endpoint 4 (composite of objectively confirmed symptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal PE, VTE-related deaths or major bleeding events up to Day 180) as adjudicated by an independent blinded CEC up-to-Day 180 observation period was reported.	Up to Day 180
Percentage of Participants With Time to the First Occurrence of Clinically Relevant Non-major Bleeding	Percentage of participants with time to the first occurrence of clinically relevant non-major bleeding was reported. Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, or unscheduled contact with a physician, or temporary cessation of study treatment, or discomfort such as pain, or impairment of activities of daily life.	From first dose of study drug to 2 days after the last dose of the study drug (up to 32 weeks)
Percentage of Participants With Time to the First Occurrence of Minor Bleeding	Percentage of participants with time to the first occurrence of minor bleeding was reported. Minor bleeding (that is, minimal bleeding) is defined as overt bleeding episodes not meeting the criteria for major or clinically relevant non-major bleeding event.	From first dose of study drug to 2 days after the last dose of the study drug (up to 32 weeks)
Percentage of Participants With Time to the First Occurrence of Any Bleeding	Percentage of participants with time to the first occurrence of any bleeding event was reported. Any bleeding is defined as a composite of major bleeding, clinically relevant non-major bleeding, or minor bleeding.	From first dose of study drug to 2 days after the last dose of the study drug (up to 32 weeks)

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: Bayer

Publications and helpful links

General Publications

• Rutjes AW, Porreca E, Candeloro M, Valeriani E, Di Nisio M. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2020 Dec 18;12(12):CD008500. doi: 10.1002/14651858.CD008500.pub5.
• Khorana AA, Barnard J, Wun T, Vijapurkar U, Damaraju CV, Moore KT, Wildgoose P, McCrae KR. Biomarker signatures in cancer patients with and without venous thromboembolism events: a substudy of CASSINI. Blood Adv. 2022 Feb 22;6(4):1212-1221. doi: 10.1182/bloodadvances.2021005710.
• Vadhan-Raj S, McNamara MG, Venerito M, Riess H, O'Reilly EM, Overman MJ, Zhou X, Vijapurkar U, Kaul S, Wildgoose P, Khorana AA. Rivaroxaban thromboprophylaxis in ambulatory patients with pancreatic cancer: Results from a pre-specified subgroup analysis of the randomized CASSINI study. Cancer Med. 2020 Sep;9(17):6196-6204. doi: 10.1002/cam4.3269. Epub 2020 Jul 14.
• Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630.
• Khorana AA, Vadhan-Raj S, Kuderer NM, Wun T, Liebman H, Soff G, Belani C, O'Reilly EM, McBane R, Eikelboom J, Damaraju CV, Beyers K, Dietrich F, Kakkar AK, Riess H, Peixoto RD, Lyman GH. Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients with Cancer: Rationale and Design of the CASSINI Trial. Rationale and Design of the CASSINI Trial. Thromb Haemost. 2017 Nov 1;117(11):2135-2145. doi: 10.1160/TH17-03-0171. Epub 2017 Sep 21.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2015
• Primary Completion (Actual): August 24, 2018
• Study Completion (Actual): August 24, 2018

Study Registration Dates

• First Submitted: September 18, 2015
• First Submitted That Met QC Criteria: September 18, 2015
• First Posted (Estimate): September 22, 2015

Study Record Updates

• Last Update Posted (Actual): September 12, 2019
• Last Update Submitted That Met QC Criteria: August 22, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Cancer; Rivaroxaban; Venous thromboembolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: CR107047; 39039039STM4001 (Other Identifier: Janssen Research & Development, LLC); 2015-001630-21 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No