<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03266783</url>
  </required_header>
  <id_info>
    <org_study_id>COBRRA</org_study_id>
    <nct_id>NCT03266783</nct_id>
  </id_info>
  <brief_title>Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism</brief_title>
  <acronym>COBRRA</acronym>
  <official_title>Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ottawa Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute&#xD;
      symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both&#xD;
      approved by Health Canada. No safety or efficacy data is available from direct head-to-head&#xD;
      comparison of these two anticoagulants. Lawsuits in the United States over bleeding events,&#xD;
      patient perceptions, and concerns with medication adherence are additional factors&#xD;
      highlighting the importance of a comparison trial. This multi-center, pragmatic, prospective,&#xD;
      randomized, open-label, blinded end-point (PROBE) trial aims to compare the safety of&#xD;
      apixaban and rivaroxaban for the treatment of VTE.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      VTE is the third leading cause of mortality by cardiovascular disease. Standard treatment for&#xD;
      acute VTE uses a combination of parenteral Low-Molecular-Weight Heparin (LMWH) and oral&#xD;
      vitamin K antagonists (VKA) for 3 months, and carries significant bleeding risk. The major&#xD;
      and/or clinically-relevant non-major bleeding (CRNMB) event rate is reported between 8.1-9.7%&#xD;
      during initial treatment. This treatment is burdensome owing to subcutaneous injections, drug&#xD;
      interactions, and laboratory monitoring. Direct oral anticoagulants (DOACs) are simpler to&#xD;
      use and do not require laboratory monitoring.&#xD;
&#xD;
      Rivaroxaban and apixaban are two DOACs targeting Factor Xa. Each DOAC was separately proven&#xD;
      effective and safe when compared to standard treatment. Comparison of the bleeding rates&#xD;
      between studies would favour use of apixaban over rivaroxaban; however, trial limitations and&#xD;
      lack of direct comparison between these two agents makes it impossible to draw firm&#xD;
      conclusions. This represents a dilemma in clinical practice because the absence of convincing&#xD;
      differences in safety has led to genuine uncertainty about which DOAC has the best&#xD;
      risk-to-benefit ratio.&#xD;
&#xD;
      To address these limitations, a head-to-head randomized controlled trial (RCT) is needed to&#xD;
      determine the safety (i.e. bleeding risk) of twice daily apixaban over once daily rivaroxaban&#xD;
      during the first 3 months of acute VTE treatment. Eligibility criteria will be less stringent&#xD;
      than the COBRRA pilot study and reflect real-world patients. Cost-effective analysis of&#xD;
      apixaban twice daily compared to rivaroxaban once daily will also be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 13, 2017</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">June 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The rate of adjudicated clinically relevant bleeding (CRB) events</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
    <description>CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adjudicated Major Bleeding events</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adjudicated Clinically Relevant Non-Major Bleeding events</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adjudicated recurrent VTE events</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adjudicated VTE-related deaths</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication adherence</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality-adjusted life years (QALYs) gained</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incremental cost-effectiveness ratio</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent</measure>
    <time_frame>For the duration of the study: 3 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">2760</enrollment>
  <condition>Venous Thromboembolism</condition>
  <arm_group>
    <arm_group_label>Apixaban group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>10 mg PO BID for 1 week, then 5 mg PO BID for 3 months of treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rivaroxaban group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>15 mg PO BID for 3 weeks, then 20 mg PO OD for 3 months of treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apixaban</intervention_name>
    <description>Refer to Apixaban group</description>
    <arm_group_label>Apixaban group</arm_group_label>
    <other_name>Eliquis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rivaroxaban</intervention_name>
    <description>Refer to Rivaroxaban group</description>
    <arm_group_label>Rivaroxaban group</arm_group_label>
    <other_name>Xarelto</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed newly diagnosed symptomatic acute VTE (proximal power extremity DVT or&#xD;
             segmental or greater PE)&#xD;
&#xD;
          -  Age ≥ 18 years old&#xD;
&#xD;
          -  Informed consent obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Have received &gt; 72 hours of therapeutic anticoagulation&#xD;
&#xD;
          -  Creatinine clearance &lt; 30 ml/min calculated with the Cockcroft-Gault formula&#xD;
&#xD;
          -  Any contraindication for anticoagulation with apixaban or rivaroxaban as determined by&#xD;
             the treating physician such as, but not limited to:&#xD;
&#xD;
               -  active bleeding,&#xD;
&#xD;
               -  active malignancy, defined as a) diagnosed with cancer within the past 6 months;&#xD;
                  or b) recurrent, regionally advanced or metastatic disease; or c) currently&#xD;
                  receiving treatment or have received any treatment for cancer during the 6 months&#xD;
                  prior to randomization; or d) a hematologic malignancy not in complete remission,&#xD;
&#xD;
               -  weight &gt; 120 kg,&#xD;
&#xD;
               -  liver disease (Child-Pugh Class B or C),&#xD;
&#xD;
               -  use of contraindicated medications&#xD;
&#xD;
               -  another indication for long-term anticoagulation (e.g. atrial fibrillation)&#xD;
&#xD;
               -  pregnant (note below) or breastfeeding (Note: as reported by the patient or a&#xD;
                  pregnancy test will be ordered at the discretion of the treating physician for&#xD;
                  women of childbearing potential as per standard of care)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lana Castellucci, MD, FRCPC</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ottawa Hospital Research Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lana Castellucci, MD, FRCPC</last_name>
    <phone>613-737-8899</phone>
    <phone_ext>74641</phone_ext>
    <email>lcastellucci@toh.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Veronica Bates, BSc, CCRP</last_name>
    <phone>613-737-8899</phone>
    <phone_ext>71068</phone_ext>
    <email>vebates@ohri.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Calgary</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Deepa Suryanarayan, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Alberta Health Sciences</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>St. Paul's Hospital</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tony Wan, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>QEII Health Science Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H 2Y9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Hamilton General Hospital</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Gross, MD</last_name>
    </contact>
    <contact_backup>
      <last_name>Sam Schulman, MD</last_name>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Juravinski Hospital</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Gross, MD</last_name>
    </contact>
    <contact_backup>
      <last_name>Sam Schulman, MD</last_name>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Healthcare Hamilton</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>James Douketis, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kingston General Hospital</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Kerstin de Wit, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>London Health Sciences Center</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5W9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Kovacs, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Ottawa Hospital - General Campus</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lana Castellucci, MD, FRCPC</last_name>
      <phone>613-737-8899</phone>
      <phone_ext>74641</phone_ext>
      <email>lcastellucci@toh.ca</email>
    </contact>
    <contact_backup>
      <last_name>Veronica Bates, BSc, CCRP</last_name>
      <phone>613-737-8899</phone>
      <phone_ext>71068</phone_ext>
      <email>vebates@ohri.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Lana Castellucci, MD, FRCPC</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UHN - Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Erik Yeo, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital Sacré-Coeur de Montréal</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Isabelle Chagnon, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>St. Mary's Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Susan Kahn, MD, FRCPC</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>McGill University Health Center</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4A 3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marc Rodger, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Québec-Université Laval</name>
      <address>
        <city>Quebec city</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Benoit Cote, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Sherbrooke</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>August 10, 2017</study_first_submitted>
  <study_first_submitted_qc>August 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>April 20, 2023</last_update_submitted>
  <last_update_submitted_qc>April 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thromboembolism</mesh_term>
    <mesh_term>Venous Thromboembolism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rivaroxaban</mesh_term>
    <mesh_term>Apixaban</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03266783
org study id: COBRRA
nct id: NCT03266783
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute
      symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both
      approved by Health Canada. No safety or efficacy data is available from direct head-to-head
      comparison of these two anticoagulants. Lawsuits in the United States over bleeding events,
      patient perceptions, and concerns with medication adherence are additional factors
      highlighting the importance of a comparison trial. This multi-center, pragmatic, prospective,
      randomized, open-label, blinded end-point (PROBE) trial aims to compare the safety of
      apixaban and rivaroxaban for the treatment of VTE.
VTE is the third leading cause of mortality by cardiovascular disease. Standard treatment for
      acute VTE uses a combination of parenteral Low-Molecular-Weight Heparin (LMWH) and oral
      vitamin K antagonists (VKA) for 3 months, and carries significant bleeding risk. The major
      and/or clinically-relevant non-major bleeding (CRNMB) event rate is reported between 8.1-9.7%
      during initial treatment. This treatment is burdensome owing to subcutaneous injections, drug
      interactions, and laboratory monitoring. Direct oral anticoagulants (DOACs) are simpler to
      use and do not require laboratory monitoring.

      Rivaroxaban and apixaban are two DOACs targeting Factor Xa. Each DOAC was separately proven
      effective and safe when compared to standard treatment. Comparison of the bleeding rates
      between studies would favour use of apixaban over rivaroxaban; however, trial limitations and
      lack of direct comparison between these two agents makes it impossible to draw firm
      conclusions. This represents a dilemma in clinical practice because the absence of convincing
      differences in safety has led to genuine uncertainty about which DOAC has the best
      risk-to-benefit ratio.

      To address these limitations, a head-to-head randomized controlled trial (RCT) is needed to
      determine the safety (i.e. bleeding risk) of twice daily apixaban over once daily rivaroxaban
      during the first 3 months of acute VTE treatment. Eligibility criteria will be less stringent
      than the COBRRA pilot study and reflect real-world patients. Cost-effective analysis of
      apixaban twice daily compared to rivaroxaban once daily will also be performed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The rate of adjudicated clinically relevant bleeding (CRB) events
time frame: For the duration of the study: 3 months
description: CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.
measure: Adjudicated Major Bleeding events
time frame: For the duration of the study: 3 months
measure: Adjudicated Clinically Relevant Non-Major Bleeding events
time frame: For the duration of the study: 3 months
measure: Adjudicated recurrent VTE events
time frame: For the duration of the study: 3 months
measure: Adjudicated VTE-related deaths
time frame: For the duration of the study: 3 months
measure: All-cause mortality
time frame: For the duration of the study: 3 months
measure: Medication adherence
time frame: For the duration of the study: 3 months
measure: Quality-adjusted life years (QALYs) gained
time frame: For the duration of the study: 3 months
measure: Incremental cost-effectiveness ratio
time frame: For the duration of the study: 3 months
measure: Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent
time frame: For the duration of the study: 3 months
arm group label: Apixaban group
arm group type: Active Comparator
description: 10 mg PO BID for 1 week, then 5 mg PO BID for 3 months of treatment
arm group label: Rivaroxaban group
arm group type: Active Comparator
description: 15 mg PO BID for 3 weeks, then 20 mg PO OD for 3 months of treatment
intervention type: Drug
intervention name: Apixaban
description: Refer to Apixaban group
arm group label: Apixaban group
other name: Eliquis
intervention type: Drug
intervention name: Rivaroxaban
description: Refer to Rivaroxaban group
arm group label: Rivaroxaban group
other name: Xarelto
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lana Castellucci, MD, FRCPC
role: Principal Investigator
affiliation: Ottawa Hospital Research Institute
last name: Lana Castellucci, MD, FRCPC
phone: 613-737-8899
phone ext: 74641
email: lcastellucci@toh.ca
last name: Veronica Bates, BSc, CCRP
phone: 613-737-8899
phone ext: 71068
email: vebates@ohri.ca
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
country: Canada
responsible party type: Sponsor
mesh term: Thromboembolism
mesh term: Venous Thromboembolism
mesh term: Rivaroxaban
mesh term: Apixaban
sharing ipd: No