Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer (CANVAS)

• ClinicalTrials.gov Identifier: NCT02744092
• Recruitment Status: Active, not recruiting
• First Posted: April 20, 2016
• Last Update Posted: May 10, 2022
• Sponsor: Alliance Foundation Trials, LLC.
• Collaborator: Patient-Centered Outcomes Research Institute
• Information provided by (Responsible Party): Alliance Foundation Trials, LLC.

Tracking Information

• First Submitted Date: April 11, 2016
• First Posted Date: April 20, 2016
• Last Update Posted Date: May 10, 2022
• Actual Study Start Date: December 2016
• Estimated Primary Completion Date: January 12, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2016)

Cumulative VTE recurrence reported by participants (via study-specific questionnaire) or clinicians (via study-specific case report form) [ Time Frame: 6 months ]

To compare the effectiveness of anticoagulation with a DOAC (intervention) with LMWH/warfarin (comparator) for preventing VTE recurrence in patients with cancer based on cumulative VTE recurrence reported by patients or clinicians at 6 months.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 15, 2016)

• Cumulative rates of major bleeding reported by participants (via study-specific questionnaire) or clinicians (via study-specific case report form) [ Time Frame: 6 months ]
  To compare the harms of DOAC vs. LMWH/warfarin therapy for cancer patients with VTE based on the cumulative rate of major bleeding at 6 months.
• Health related quality of life reported by participants via the Optum SF-12v2 Health Survey questionnaire [ Time Frame: 3 and 6 months ]
  To compare the impact of DOAC vs. LMWH/warfarin therapy on the health related quality of life (HRQOL) for cancer patients with VTE at 3 and 6 months.
• Burden of anticoagulation therapy reported by participants via the Anti-Clot Treatment Scale (ACTS) questionnaire [ Time Frame: 3 and 6 months ]
  To compare the burden of anticoagulation therapy with DOAC vs. with LMWH/warfarin for cancer patients with VTE at 3 and 6 months.
• Mortality reported by participants' surrogates (via study-specific questionnaire) or clinicians (via study-specific case report form) [ Time Frame: 6 months ]
  To compare the impact of DOAC vs. LMWH/warfarin therapy on mortality in cancer patients with VTE based on survival at 6 months.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer
• Official Title: Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer: A Randomized Effectiveness Trial (CANVAS Trial)
• Brief Summary: The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The intervention strategy is Direct Oral AntiCoagulants (DOAC) therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is low molecular weight heparin (LMWH) alone or with warfarin. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.

Detailed Description

Venous blood clots affect nearly a million Americans each year. Venous clots in the legs are called deep venous thrombosis (DVT) and are dangerous because they travel to the lungs where they cause blockages known as pulmonary emboli (PE). DVT and PE are called venous thromboemboli (VTE). Cancer is a risk factor with nearly 200,000 VTEs in cancer patients each year. The purpose of VTE treatment is to prevent the initial clot from spreading and to prevent new clots from forming. This is accomplished by thinning the blood, or anticoagulation. Without anticoagulation, VTEs recur and are often fatal.

Recently, the FDA has approved 4 new Direct Oral AntiCoagulants (DOACs) for preventing VTE recurrence. Few cancer patients were included in the efficacy trials, and practice guidelines fall silent on whether switching to DOAC therapy is advisable. To fill this knowledge gap, the Alliance Foundation Trials LLC, a research network of academic and community practices across the US, is conducting a pragmatic randomized effectiveness trial.

The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The investigators will conduct a trial of 811 cancer patients followed for 6 months. The intervention strategy is DOAC therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is LMWH alone or with warfarin. Within each arm, patients can choose the agent they prefer based on side effects, drug interactions, and practical issues such as co-pays. The trial compares these two strategies in terms of treatment: 1) benefits based on VTE recurrence; 2) harms based on bleeding rates; 3) burdens based on patients' reports of their experiences; and 4) mortality rates.

The investigators hypothesize that the benefits, harms and burdens of DOAC treatment will be non-inferior to, or better than, usual care with LMWH/ warfarin among cancer patients. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Cancer
• Venous Thromboembolism
• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)
• Blood Clot

Intervention

• Drug: Rivaroxaban
  Anticoagulation therapy.
  Other Name: Xarelto
• Drug: Apixaban
  Anticoagulation therapy.
  Other Name: Eliquis
• Drug: Edoxaban
  Anticoagulation therapy.
  Other Name: Savaysa
• Drug: Dabigatran
  Anticoagulation therapy.
  Other Name: Pradaxa
• Drug: Warfarin
  Anticoagulation therapy.
  Other Name: Coumadin
• Drug: Dalteparin
  Anticoagulation therapy.
  Other Name: Fragmin
• Drug: Enoxaparin
  Anticoagulation therapy.
  Other Name: Lovenox
• Drug: Fondaparinux
  Anticoagulation therapy.
  Other Name: Arixtra

Study Arms

• Experimental: Randomized Arm 1
  Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator.
  Interventions:

  • Drug: Rivaroxaban
  • Drug: Apixaban
  • Drug: Edoxaban
  • Drug: Dabigatran
• Active Comparator: Randomized Arm 2
  Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator.
  Interventions:

  • Drug: Warfarin
  • Drug: Dalteparin
  • Drug: Enoxaparin
  • Drug: Fondaparinux
• Experimental: Preference Cohort

  If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized).

  Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC).

  Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin.

  Interventions:

  • Drug: Rivaroxaban
  • Drug: Apixaban
  • Drug: Edoxaban
  • Drug: Dabigatran
  • Drug: Warfarin
  • Drug: Dalteparin
  • Drug: Enoxaparin
  • Drug: Fondaparinux

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 11, 2020): 811
• Original Estimated Enrollment (submitted: April 15, 2016): 940
• Estimated Study Completion Date: January 12, 2023
• Estimated Primary Completion Date: January 12, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of advanced solid tumor cancer, lymphoma, or myeloma (no time restrictions or limitations) -OR- diagnosis of early stage solid tumor cancer, lymphoma, or myeloma <= 12 months prior to study enrollment

• Diagnosis of VTE <= 30 days prior to study enrollment for which potential benefits of anticoagulation therapy to prevent recurrence of VTE are felt by the treating physician to exceed the potential harms

  • Any anticoagulation drug/strategy may be used to treat the index VTE; protocol treatment will begin <= 30days after the index VTE diagnosis date
• Treating physician intends to put participant on anticoagulation therapy for at least three months.
• Age >= 18 years
• Platelet count is >= 50,000/mm^3 (<= 7 days prior to enrollment)
• CrCl (Creatinine Clearance) is >= 15 ml/min (<= 7 days prior to enrollment)

Exclusion Criteria:

• Diagnosis of acute leukemia

• Has ever received or is scheduled to receive an Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)

  • Patients who have ever received an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) ARE eligible.
  • Patients who are scheduled to receive an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) are NOT eligible
• Ongoing, clinically significant bleeding (CTCAE grade 3 or 4)
• Ongoing therapy with a P-gp inhibitor (e.g., nelfinavir, indinavir, or saquinavir-protease inhibitors for HIV) as these drugs interact with the factor Xa inhibitors
• Therapy with any azole antifungals (e.g., itraconazole, ketaconazole, voriconazole) at the time of enrollment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02744092
• Other Study ID Numbers: AFT-28; CER-1503-29805 ( Other Grant/Funding Number: Patient-Centered Outcomes Research Institute (PCORI) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: Individual-level de-identified datasets will be made available to investigators working under an institution with a Federal Wide Assurance (FWA) who formally submit a request to Alliance Foundation Trials LLC (AFT). Prior to the release of datasets, AFT ensures certain requirements, e.g., IRB approval and data use agreement, are in place. These datasets will be available within 6 months of publication of the manuscript and following a formal request by an investigator to and approval from AFT.

• Current Responsible Party: Alliance Foundation Trials, LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance Foundation Trials, LLC.
• Original Study Sponsor: Same as current
• Collaborators: Patient-Centered Outcomes Research Institute

Investigators

• Study Chair: Deborah Schrag, MD MPH; Alliance Foundation Trials, LLC.
• Study Chair: Jean Connors, MD; Alliance Foundation Trials, LLC.

• PRS Account: Alliance Foundation Trials, LLC.
• Verification Date: May 2022