<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/NCT03240120</url>
  </required_header>
  <id_info>
    <org_study_id>HKU-OTI-01</org_study_id>
    <nct_id>NCT03240120</nct_id>
  </id_info>
  <brief_title>A Study of Dabigatran Etexilate as Primary Treatment of Malignancy Associated Venous Thromboembolism</brief_title>
  <official_title>A Prospective Study of Dabigatran Etexilate as Primary Treatment of Malignancy Associated Venous Thromboembolism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>No</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>
      This trial aims at determining if dabigatran is effective in the treatment of malignancy&#xD;
      associated VTE. Tolerance and safety of dabigatran will also be assessed.&#xD;
&#xD;
      This is a single armed trial of dabigatran in patients with malignancy associated VTE.&#xD;
&#xD;
      The target recruitment is 99 consecutive patients with active malignancy and newly diagnosed&#xD;
      VTE (deep vein thrombosis and/or pulmonary embolism) in Queen Mary Hospital.&#xD;
&#xD;
      Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed (duplex&#xD;
      Doppler ultrasonography for deep vein thrombosis, and computed tomography for pulmonary&#xD;
      embolism), and a written consent is obtained. Patients will be switched to dabigatran 150mg&#xD;
      twice daily from day 6 onwards. The first dose of dabigatran will be given within 2 hours&#xD;
      before the time that the next dose of tinzaparin would have been due. Anticoagulation will be&#xD;
      continued as long as malignancy is active. If patients achieve a complete remission of their&#xD;
      underlying malignancies, dabigatran will be continued for 6 months further.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with malignancies are at increased risks of venous thromboembolism (VTE). The annual&#xD;
      incidence of VTE in cancer patients is 0.5%, which is 5-fold more than the general population&#xD;
      . Low molecular weight heparin (LMWH) has been the standard treatment for&#xD;
      malignancy-associated VTE. This recommendation follows the results of the Randomized&#xD;
      Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the&#xD;
      Prevention of Recurrent VenousThromboembolism in Patients with Cancer (CLOT) trial, which&#xD;
      showed superiority of Low molecular weight heparin (LMWH) over warfarin in cancer patients&#xD;
      with VTE .&#xD;
&#xD;
      Low molecular weight heparin (LMWH) has a number of inherent advantages over warfarin. It&#xD;
      does not interact with chemotherapeutic agents, and dose titration is not necessary.&#xD;
      Furthermore, the risks of both bleeding and breakthrough VTE are also lower with LMWH.&#xD;
      However, the requirement of daily subcutaneous injection makes LWMH inconvenient to use. Most&#xD;
      patients have difficulties continuing daily injection, partly owing to compliance issues, but&#xD;
      also because an emaciated state in some patients makes subcutaneous injection painful. As the&#xD;
      life expectancy of solid cancer patients is improved with novel treatment options, the choice&#xD;
      of anticoagulation has become a major issue in the management of VTE in this patient&#xD;
      population.&#xD;
&#xD;
      The main reason underlying the inferior performance of warfarin in oncology patients is&#xD;
      difficult dose titration. Drug interaction and hepatic dysfunction are common in patients on&#xD;
      chemotherapy. Frequent interruptions of warfarin for invasive procedures and&#xD;
      chemotherapy-induced-thrombocytopenia also lead to fluctuations in anticoagulation level. As&#xD;
      a result, highs risk of recurrence of VTE and bleeding were observed in cancer patients&#xD;
      taking warfarin. Direct-acting oral anticoagulants (DOACs), on the other hand, may be an&#xD;
      attractive alternative treatment to LMWH. They are administered at a fixed dose with&#xD;
      predictable pharmacokinetics, so that therapeutic monitoring is not required. There is&#xD;
      minimal food and drug interaction. They have been shown to be effective in the treatment of&#xD;
      VTE in several pivotal randomized controlled trials in comparison with warfarin . However,&#xD;
      their role in malignancy associated VTE is yet to be determined, because cancer patients were&#xD;
      either excluded or very much underrepresented in these VTE treatment trials. Moreover, the&#xD;
      non-inferiority of DOACs in VTE treatment was only demonstrated against warfarin, which is&#xD;
      already shown to be suboptimal in oncology patients. A trial directly comparing DOACs with&#xD;
      LMWH in malignancy associated VTE is therefore needed.&#xD;
&#xD;
      Dabigatran etexilate is an oral thrombin inhibitor. It was shown in the RECOVER study to be&#xD;
      effective in treatment of VTE and it has a lower bleeding risk than warfarin. It is not&#xD;
      metabolized by cytochrome P450 system and therefore, in contrast to other DOACs, concomitant&#xD;
      administration of CYP3A4 inducers or inhibitors is not a concern.&#xD;
&#xD;
      We propose this prospective single armed trial to evaluate the efficacy and safety of&#xD;
      dabigatran in the treatment of malignancy associated VTE. We will compare the result with our&#xD;
      historical control who were treated with LMWH.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2021</primary_completion_date>
  <phase>Phase 3</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>Number of patients with symptomatic VTE</measure>
    <time_frame>up to 2 years</time_frame>
    <description>first episode of objectively documented symptomatic recurrent VTE (deep vein thrombosis, pulmonary embolism)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>number of mortality, clinically relevant major and non-major bleeding</measure>
    <time_frame>up to 2 years</time_frame>
    <description>bleeding (major and non-major) and death</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">99</enrollment>
  <condition>Venous Thromboembolism</condition>
  <condition>Deep Vein Thrombosis</condition>
  <condition>Pulmonary Embolism</condition>
  <arm_group>
    <arm_group_label>Dabigatran etexilate &amp; Tinzaparin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed dabigatran 150mg twice daily from Day 6 onward till 6 months after underlying disease remission.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabigatran etexilate</intervention_name>
    <description>Pradaxa 150 mg hard capsules</description>
    <arm_group_label>Dabigatran etexilate &amp; Tinzaparin</arm_group_label>
    <other_name>Pradaxa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tinzaparin</intervention_name>
    <description>Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed</description>
    <arm_group_label>Dabigatran etexilate &amp; Tinzaparin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. are aged 18 years or above;&#xD;
&#xD;
          2. have acute symptomatic deep vein thrombosis or pulmonary embolism with objective&#xD;
             confirmation;&#xD;
&#xD;
          3. have active cancer, which is defined as a diagnosis of cancer other than basal cell or&#xD;
             squamous cell carcinoma of skin within six months before enrollment, any treatment for&#xD;
             cancer within the previous six months or recurrent or metastatic cancer.&#xD;
&#xD;
          4. Female subjects of childbearing potential should be willing to use 2 methods of birth&#xD;
             control or be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 120 days after the last dose of study medication. Subjects of&#xD;
             childbearing potential are those who have not been surgically sterilized or have not&#xD;
             been free from menses for &gt; 1 year.&#xD;
&#xD;
          5. Male subjects should agree to use an adequate method of contraception starting with&#xD;
             the first dose of study therapy through 120 days after the last dose of study therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. have Eastern Cooperative Oncology Group (ECOG) performance status score of &gt; 2 at the&#xD;
             time of randomization;&#xD;
&#xD;
          2. have life expectancy of less than 3 months;&#xD;
&#xD;
          3. have active bleeding, are at high risk of bleeding, or have contraindications to&#xD;
             anticoagulant treatment;&#xD;
&#xD;
          4. receive thrombectomy or fibrinolytic agent to treat the current episode of VTE;&#xD;
&#xD;
          5. receive more than 72 hours pre-treatment with therapeutic dosages of anticoagulant&#xD;
             treatment prior to randomization to treat the current VTE episode;&#xD;
&#xD;
          6. are already on long term oral anticoagulation;&#xD;
&#xD;
          7. are on low molecular weight heparin for indications other than VTE;&#xD;
&#xD;
          8. have platelet count of less than 100 x 109/L;&#xD;
&#xD;
          9. are on dual antiplatelet therapy;&#xD;
&#xD;
         10. have a serum creatinine level of more than 220 umol/L or have a calculated creatinine&#xD;
             clearance (CrCl) of less than 30 ml/min;&#xD;
&#xD;
         11. have alanine aminotransferase level more than 2 times the upper limit of normal range&#xD;
             or cirrhosis;&#xD;
&#xD;
         12. have history of heparin induced thrombocytopenia;&#xD;
&#xD;
         13. are on treatment of potent inhibitors or inducers of P-glycoprotein.&#xD;
&#xD;
         14. Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the screening visit through 120 days&#xD;
             after the last dose of trial treatment.&#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>Gloria Hwang, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Gloria Hwang, MBBS</last_name>
    <phone>852 22553111</phone>
    <phone_ext>4826</phone_ext>
    <email>yyhwang922@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Crosby Lu, MMedSc</last_name>
    <phone>852 22553111</phone>
    <phone_ext>1654</phone_ext>
    <email>khlu@hku.hk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>The University of Hong Kong</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gloria Hwang, MBBS</last_name>
      <phone>852 22553111</phone>
      <phone_ext>4826</phone_ext>
      <email>yyhwang922@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Crosby Lu, MMedSc</last_name>
      <phone>852 22553111</phone>
      <phone_ext>1654</phone_ext>
      <email>khlu@hku.hk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2017</study_first_posted>
  <last_update_submitted>April 15, 2019</last_update_submitted>
  <last_update_submitted_qc>April 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Dr. Eric W.C. Tse</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Embolism</mesh_term>
    <mesh_term>Thrombosis</mesh_term>
    <mesh_term>Embolism</mesh_term>
    <mesh_term>Thromboembolism</mesh_term>
    <mesh_term>Venous Thromboembolism</mesh_term>
    <mesh_term>Venous Thrombosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tinzaparin</mesh_term>
    <mesh_term>Heparin, Low-Molecular-Weight</mesh_term>
    <mesh_term>Dalteparin</mesh_term>
    <mesh_term>Dabigatran</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03240120
org study id: HKU-OTI-01
nct id: NCT03240120
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This trial aims at determining if dabigatran is effective in the treatment of malignancy
      associated VTE. Tolerance and safety of dabigatran will also be assessed.

      This is a single armed trial of dabigatran in patients with malignancy associated VTE.

      The target recruitment is 99 consecutive patients with active malignancy and newly diagnosed
      VTE (deep vein thrombosis and/or pulmonary embolism) in Queen Mary Hospital.

      Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed (duplex
      Doppler ultrasonography for deep vein thrombosis, and computed tomography for pulmonary
      embolism), and a written consent is obtained. Patients will be switched to dabigatran 150mg
      twice daily from day 6 onwards. The first dose of dabigatran will be given within 2 hours
      before the time that the next dose of tinzaparin would have been due. Anticoagulation will be
      continued as long as malignancy is active. If patients achieve a complete remission of their
      underlying malignancies, dabigatran will be continued for 6 months further.
Patients with malignancies are at increased risks of venous thromboembolism (VTE). The annual
      incidence of VTE in cancer patients is 0.5%, which is 5-fold more than the general population
      . Low molecular weight heparin (LMWH) has been the standard treatment for
      malignancy-associated VTE. This recommendation follows the results of the Randomized
      Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the
      Prevention of Recurrent VenousThromboembolism in Patients with Cancer (CLOT) trial, which
      showed superiority of Low molecular weight heparin (LMWH) over warfarin in cancer patients
      with VTE .

      Low molecular weight heparin (LMWH) has a number of inherent advantages over warfarin. It
      does not interact with chemotherapeutic agents, and dose titration is not necessary.
      Furthermore, the risks of both bleeding and breakthrough VTE are also lower with LMWH.
      However, the requirement of daily subcutaneous injection makes LWMH inconvenient to use. Most
      patients have difficulties continuing daily injection, partly owing to compliance issues, but
      also because an emaciated state in some patients makes subcutaneous injection painful. As the
      life expectancy of solid cancer patients is improved with novel treatment options, the choice
      of anticoagulation has become a major issue in the management of VTE in this patient
      population.

      The main reason underlying the inferior performance of warfarin in oncology patients is
      difficult dose titration. Drug interaction and hepatic dysfunction are common in patients on
      chemotherapy. Frequent interruptions of warfarin for invasive procedures and
      chemotherapy-induced-thrombocytopenia also lead to fluctuations in anticoagulation level. As
      a result, highs risk of recurrence of VTE and bleeding were observed in cancer patients
      taking warfarin. Direct-acting oral anticoagulants (DOACs), on the other hand, may be an
      attractive alternative treatment to LMWH. They are administered at a fixed dose with
      predictable pharmacokinetics, so that therapeutic monitoring is not required. There is
      minimal food and drug interaction. They have been shown to be effective in the treatment of
      VTE in several pivotal randomized controlled trials in comparison with warfarin . However,
      their role in malignancy associated VTE is yet to be determined, because cancer patients were
      either excluded or very much underrepresented in these VTE treatment trials. Moreover, the
      non-inferiority of DOACs in VTE treatment was only demonstrated against warfarin, which is
      already shown to be suboptimal in oncology patients. A trial directly comparing DOACs with
      LMWH in malignancy associated VTE is therefore needed.

      Dabigatran etexilate is an oral thrombin inhibitor. It was shown in the RECOVER study to be
      effective in treatment of VTE and it has a lower bleeding risk than warfarin. It is not
      metabolized by cytochrome P450 system and therefore, in contrast to other DOACs, concomitant
      administration of CYP3A4 inducers or inhibitors is not a concern.

      We propose this prospective single armed trial to evaluate the efficacy and safety of
      dabigatran in the treatment of malignancy associated VTE. We will compare the result with our
      historical control who were treated with LMWH.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with symptomatic VTE
time frame: up to 2 years
description: first episode of objectively documented symptomatic recurrent VTE (deep vein thrombosis, pulmonary embolism)
measure: number of mortality, clinically relevant major and non-major bleeding
time frame: up to 2 years
description: bleeding (major and non-major) and death
arm group label: Dabigatran etexilate & Tinzaparin
arm group type: Experimental
description: Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed dabigatran 150mg twice daily from Day 6 onward till 6 months after underlying disease remission.
intervention type: Drug
intervention name: Dabigatran etexilate
description: Pradaxa 150 mg hard capsules
arm group label: Dabigatran etexilate & Tinzaparin
other name: Pradaxa
intervention type: Drug
intervention name: Tinzaparin
description: Tinzaparin 175 iu/kg daily will be started after the diagnosis of VTE is confirmed
arm group label: Dabigatran etexilate & Tinzaparin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gloria Hwang, MBBS
role: Principal Investigator
affiliation: The University of Hong Kong
last name: Gloria Hwang, MBBS
phone: 852 22553111
phone ext: 4826
email: yyhwang922@gmail.com
last name: Crosby Lu, MMedSc
phone: 852 22553111
phone ext: 1654
email: khlu@hku.hk
facility: 
status: Recruiting
contact: 
contact backup: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Dr. Eric W.C. Tse
investigator title: Clinical Professor
mesh term: Pulmonary Embolism
mesh term: Thrombosis
mesh term: Embolism
mesh term: Thromboembolism
mesh term: Venous Thromboembolism
mesh term: Venous Thrombosis
mesh term: Tinzaparin
mesh term: Heparin, Low-Molecular-Weight
mesh term: Dalteparin
mesh term: Dabigatran
sharing ipd: Undecided