<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/NCT03297359</url>
  </required_header>
  <id_info>
    <org_study_id>WAVe-001</org_study_id>
    <nct_id>NCT03297359</nct_id>
  </id_info>
  <brief_title>WAVe Study - Weight Adjusted Dalteparin for Patients Over 90 kg With Acute Cancer Associated Venous Thromboembolism</brief_title>
  <acronym>WAVe</acronym>
  <official_title>A Multicentre Prospective Cohort Study Assessing the Use of Weight-Adjusted Low-Molecular-Weight-Heparin in Patients Over 90 kg With Acute Cancer-Associated Venous Thromboembolism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cancer patients that develop blood clots are treated with low molecular weight heparin&#xD;
      injections (LMWH). One kind of these LMWHs, dalteparin, has its dose determined based on a&#xD;
      patient's weight using a formula of 200 international units (IU) per kilogram (kg). The&#xD;
      current dosing of dalteparin approved by Health Canada has a maximum daily dose of 18 000&#xD;
      IU/day which is weight-adjusted for patients up to 90 kg. Any patient weighing more than 90&#xD;
      kg would take the same dosage regardless of their weight. The aim of this study is to assess&#xD;
      the safety of using weight-adjusted dalteparin in cancer-associated venous thromboembolism&#xD;
      patients that weigh more than 90 kg.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is designed as a multicentre prospective cohort study with multiple Canadian sites.&#xD;
      It will be initiated at The Ottawa Hospital prior to being offered externally. After&#xD;
      obtaining informed consent, and confirming eligibility, participants weighing more than 90 kg&#xD;
      with acute cancer-associated thrombosis will be treated with therapeutic weight-adjusted&#xD;
      dalteparin (subcutaneous once daily injection, or twice daily, if the conditions of the&#xD;
      participant do not allow once daily injection as per clinical judgement) beginning at&#xD;
      enrolment (within 12 hours) and continuing until Day 30 visit. Subjects will receive&#xD;
      therapeutic doses of dalteparin at a dose of approximately 200 IU/kg SC daily (up to 33,000&#xD;
      IU) for one month. Following this study period of 30 days (± 4 days), patients will be&#xD;
      followed for 5 months. During the follow-up period, each patient will pursue his/her&#xD;
      treatment as per usual standard treatment protocols provided at each institution. Treatment&#xD;
      used and clinical outcomes will be collected at the end of the follow-up period.&#xD;
&#xD;
      The majority of Canadian Thrombosis specialists use weight adjusted dosing of dalteparin in&#xD;
      patients weighing more than 90 kg with cancer-associated VTE. No expert recommends capping&#xD;
      the dose of dalteparin to 18,000 IU in patients weighing over 90 kg as suggested by the&#xD;
      product monograph. However, the risk of major bleeding episodes in patients over 90 kg&#xD;
      receiving weight-adjusted LMWH remains unclear. The estimated rate of major bleeding episodes&#xD;
      of patients with cancer associated VTE (Mean weight 79.1 kg) managed with therapeutic dose of&#xD;
      dalteparin is 3.6% (95% CI: 1.9 to 6.2). We hypothesize that the rate of major bleeding&#xD;
      events will be similar in patients (&gt; 90 kg) with cancer-associated VTE treated with&#xD;
      dalteparin 200 IU/kg daily (up to 33,000 IU). We plan to recruit 150 patients in this cohort&#xD;
      study. We expect 6 major bleeding events. This would provide us with an overall bleeding&#xD;
      event of 4% with an upper bound of the confidence interval of 8.5%). An informal survey of&#xD;
      Canadian thrombosis expert has demonstrated that clinicians would feel reassured and continue&#xD;
      to use weight-adjusted dalteparin in cancer patients weighing more than 90kg if the upper&#xD;
      bound of the 95% confidence interval is less than 9% (i.e. &lt; 3% possible absolute rate&#xD;
      difference).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 21, 2018</start_date>
  <completion_date type="Anticipated">June 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Major bleeding episode</measure>
    <time_frame>up to day 30</time_frame>
    <description>Fatal bleeding, and/or,&#xD;
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or,&#xD;
Bleeding causing a fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinically relevant non major bleeding events</measure>
    <time_frame>up to day 30</time_frame>
    <description>As overt bleeding episodes not meeting the inclusion for major bleeding but associated with one of the following:&#xD;
Medical intervention,&#xD;
An unscheduled contact with a physician,&#xD;
Temporary cessation of anticoagulant treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minor bleeding events</measure>
    <time_frame>up to day 30</time_frame>
    <description>Overt bleeding not meeting the major bleeding or clinically-relevant non-major bleeding definitions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrent VTE events</measure>
    <time_frame>Up to day 180</time_frame>
    <description>Recurrent deep vein thrombosis&#xD;
Recurrent Pulmonary embolism</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall mortality</measure>
    <time_frame>Up to day 180</time_frame>
    <description>Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bioaccumulation of study drug</measure>
    <time_frame>Up to day 30</time_frame>
    <description>Trough anti-Xa levels measured at Day 7 and Day 30 follow-up visits will be generated for the once and twice-daily dosing regimen</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Cancer</condition>
  <condition>Venous Thromboembolism</condition>
  <condition>Obesity</condition>
  <arm_group>
    <arm_group_label>Weight adjusted dalteparin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a daily subcutaneous injection of weight-adjusted dalteparin (See Table below) at a dose of approx. 200 IU/kg beginning on the day of enrolment and for a one month.&#xD;
91 to 95 kg: 18,000 IU daily ( or 1 prefilled syringe of 18,000 IU) 96 to 105 kg: 20,000 IU daily ( or 2 prefilled syringes of 10,000 IU) 106 to 120 kg: 22,500 IU daily ( or 2 pre-filled syringes (10,000 and 12,500 IU)) 121 to 130 kg: 25,000 IU daily ( or 2 prefilled syringes of 12,500 IU) 131 to 145 kg: 27,500 IU daily ( or 2 pre-filled syringes (12,500 and 15,000 IU)) 146 to 150 kg: 30,000 IU daily ( or 2 prefilled syringes of 15,000 IU)&#xD;
≥ 151 kg: 33,000 IU daily ( or 2 prefilled syringes (15,000 and 18,000 IU))</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Dalteparin</intervention_name>
    <description>daily subcutaneous injection of weight-adjusted dalteparin</description>
    <arm_group_label>Weight adjusted dalteparin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Known pathologically-confirmed cancer (other than basal-cell or squamous-cell&#xD;
             carcinoma of the skin),&#xD;
&#xD;
          2. Confirmed symptomatic or incidental deep vein thrombosis requiring treatment, or&#xD;
             confirmed symptomatic or incidental pulmonary embolism of a segmental or larger&#xD;
             pulmonary artery,&#xD;
&#xD;
          3. Weight &gt; 90 kg,&#xD;
&#xD;
          4. Age ≥18 years,&#xD;
&#xD;
          5. Hemoglobin ≥ 80 g/L,&#xD;
&#xD;
          6. Able and willing to comply with study procedures and follow-up examinations contained&#xD;
             within the written consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Acute VTE managed with thrombectomy, insertion of an inferior vena cava filter or with&#xD;
             the use of thrombolytic agents,&#xD;
&#xD;
          2. More than 72 hours pre-treatment with therapeutic dosage of other LMWH, direct oral&#xD;
             anticoagulants or vitamin K antagonists prior to enrolment to manage the current VTE&#xD;
             event (unless the participant has been treated with weight-adjusted doses of&#xD;
             commercial dalteparin in consistency with the dosing regime outlined in the protocol&#xD;
             up to Day 7 visit [±2 days]),&#xD;
&#xD;
          3. Contraindication to heparin therapy:&#xD;
&#xD;
               1. history of heparin induced thrombocytopenia (HIT) as reported by patient,&#xD;
&#xD;
               2. platelet count of less than 50 x 109/L,&#xD;
&#xD;
               3. actively bleeding,&#xD;
&#xD;
               4. reported history of severe uncontrolled hypertension,&#xD;
&#xD;
               5. documented peptic ulcer within 6 weeks,&#xD;
&#xD;
               6. reported history of severe hepatic failure,&#xD;
&#xD;
               7. creatinine clearance of &lt; 30 ml/min as calculated by the Cockcroft-Gault formula,&#xD;
&#xD;
               8. heparin allergy,&#xD;
&#xD;
               9. Other contraindication to anticoagulation.&#xD;
&#xD;
          4. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 or 4 at the time&#xD;
             of study enrolment,&#xD;
&#xD;
          5. Life expectancy &lt; 1 month,&#xD;
&#xD;
          6. Women of childbearing age without proper contraceptive measures and women who are&#xD;
             pregnant or breast feeding,&#xD;
&#xD;
          7. Participating in another interventional trial that may result in co-intervention or&#xD;
             contamination (to be determined by sponsor),&#xD;
&#xD;
          8. Unable/unwilling to provide informed consent.&#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>Marc Carrier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ottawa Hospital Research Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Limmy Lobo, MSc</last_name>
    <phone>613-737-8899</phone>
    <phone_ext>72103</phone_ext>
    <email>llobo@ohri.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>Alberta Health Services</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2V2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cynthia Wu, MD, FRCPC</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Nova Scotia Health Authority</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H 1V7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sudeep Shivakumar, MD, FRCPC</last_name>
    </contact>
  </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, FRCPC</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Ottawa Hospital</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yan He, MSc</last_name>
    </contact>
    <investigator>
      <last_name>Marc Carrier, MD, FRCPC</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Toronto General Hopsital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1J6</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Erik Yeo, MD, FRCPC</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 26, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <last_update_submitted>March 16, 2023</last_update_submitted>
  <last_update_submitted_qc>March 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Dalteparin</keyword>
  <keyword>Fragmin</keyword>
  <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>Dalteparin</mesh_term>
    <mesh_term>Tinzaparin</mesh_term>
    <mesh_term>Heparin, Low-Molecular-Weight</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03297359
org study id: WAVe-001
nct id: NCT03297359
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Cancer patients that develop blood clots are treated with low molecular weight heparin
      injections (LMWH). One kind of these LMWHs, dalteparin, has its dose determined based on a
      patient's weight using a formula of 200 international units (IU) per kilogram (kg). The
      current dosing of dalteparin approved by Health Canada has a maximum daily dose of 18 000
      IU/day which is weight-adjusted for patients up to 90 kg. Any patient weighing more than 90
      kg would take the same dosage regardless of their weight. The aim of this study is to assess
      the safety of using weight-adjusted dalteparin in cancer-associated venous thromboembolism
      patients that weigh more than 90 kg.
The study is designed as a multicentre prospective cohort study with multiple Canadian sites.
      It will be initiated at The Ottawa Hospital prior to being offered externally. After
      obtaining informed consent, and confirming eligibility, participants weighing more than 90 kg
      with acute cancer-associated thrombosis will be treated with therapeutic weight-adjusted
      dalteparin (subcutaneous once daily injection, or twice daily, if the conditions of the
      participant do not allow once daily injection as per clinical judgement) beginning at
      enrolment (within 12 hours) and continuing until Day 30 visit. Subjects will receive
      therapeutic doses of dalteparin at a dose of approximately 200 IU/kg SC daily (up to 33,000
      IU) for one month. Following this study period of 30 days (± 4 days), patients will be
      followed for 5 months. During the follow-up period, each patient will pursue his/her
      treatment as per usual standard treatment protocols provided at each institution. Treatment
      used and clinical outcomes will be collected at the end of the follow-up period.

      The majority of Canadian Thrombosis specialists use weight adjusted dosing of dalteparin in
      patients weighing more than 90 kg with cancer-associated VTE. No expert recommends capping
      the dose of dalteparin to 18,000 IU in patients weighing over 90 kg as suggested by the
      product monograph. However, the risk of major bleeding episodes in patients over 90 kg
      receiving weight-adjusted LMWH remains unclear. The estimated rate of major bleeding episodes
      of patients with cancer associated VTE (Mean weight 79.1 kg) managed with therapeutic dose of
      dalteparin is 3.6% (95% CI: 1.9 to 6.2). We hypothesize that the rate of major bleeding
      events will be similar in patients (> 90 kg) with cancer-associated VTE treated with
      dalteparin 200 IU/kg daily (up to 33,000 IU). We plan to recruit 150 patients in this cohort
      study. We expect 6 major bleeding events. This would provide us with an overall bleeding
      event of 4% with an upper bound of the confidence interval of 8.5%). An informal survey of
      Canadian thrombosis expert has demonstrated that clinicians would feel reassured and continue
      to use weight-adjusted dalteparin in cancer patients weighing more than 90kg if the upper
      bound of the 95% confidence interval is less than 9% (i.e. < 3% possible absolute rate
      difference).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Major bleeding episode
time frame: up to day 30
description: Fatal bleeding, and/or,
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or,
Bleeding causing a fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.
measure: Clinically relevant non major bleeding events
time frame: up to day 30
description: As overt bleeding episodes not meeting the inclusion for major bleeding but associated with one of the following:
Medical intervention,
An unscheduled contact with a physician,
Temporary cessation of anticoagulant treatment.
measure: Minor bleeding events
time frame: up to day 30
description: Overt bleeding not meeting the major bleeding or clinically-relevant non-major bleeding definitions
measure: Recurrent VTE events
time frame: Up to day 180
description: Recurrent deep vein thrombosis
Recurrent Pulmonary embolism
measure: Overall mortality
time frame: Up to day 180
description: Death
measure: Bioaccumulation of study drug
time frame: Up to day 30
description: Trough anti-Xa levels measured at Day 7 and Day 30 follow-up visits will be generated for the once and twice-daily dosing regimen
arm group label: Weight adjusted dalteparin
arm group type: Experimental
description: Participants will receive a daily subcutaneous injection of weight-adjusted dalteparin (See Table below) at a dose of approx. 200 IU/kg beginning on the day of enrolment and for a one month.
91 to 95 kg: 18,000 IU daily ( or 1 prefilled syringe of 18,000 IU) 96 to 105 kg: 20,000 IU daily ( or 2 prefilled syringes of 10,000 IU) 106 to 120 kg: 22,500 IU daily ( or 2 pre-filled syringes (10,000 and 12,500 IU)) 121 to 130 kg: 25,000 IU daily ( or 2 prefilled syringes of 12,500 IU) 131 to 145 kg: 27,500 IU daily ( or 2 pre-filled syringes (12,500 and 15,000 IU)) 146 to 150 kg: 30,000 IU daily ( or 2 prefilled syringes of 15,000 IU)
≥ 151 kg: 33,000 IU daily ( or 2 prefilled syringes (15,000 and 18,000 IU))
intervention type: Biological
intervention name: Dalteparin
description: daily subcutaneous injection of weight-adjusted dalteparin
arm group label: Weight adjusted dalteparin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marc Carrier, MD
role: Principal Investigator
affiliation: Ottawa Hospital Research Institute
last name: Limmy Lobo, MSc
phone: 613-737-8899
phone ext: 72103
email: llobo@ohri.ca
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Sponsor
mesh term: Thromboembolism
mesh term: Venous Thromboembolism
mesh term: Dalteparin
mesh term: Tinzaparin
mesh term: Heparin, Low-Molecular-Weight