<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/NCT03005444</url>
  </required_header>
  <id_info>
    <org_study_id>APPROACH</org_study_id>
    <nct_id>NCT03005444</nct_id>
  </id_info>
  <brief_title>Anticoagulation for Advanced Cirrhotic Patients After TIPS</brief_title>
  <official_title>Anticoagulation for Development of Further Decompensation and Survival in Advanced Cirrhosis After Transjugular Intrahepatic Portosystemic Shunt: a Multicenter Randomized Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Air Force Military Medical University, China</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Air Force Military Medical University, China</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>
      Recent studies demonstrated that liver cirrhosis was associated with a hypercoagulability&#xD;
      state. Besides, bacterial translocation plays an important role in the pathogenesis and&#xD;
      complications in patients with decompensated cirrhosis, including infections as well as&#xD;
      hepatic encephalopathy and hepatorenal syndrome.&#xD;
&#xD;
      A recent prospective study in a group of 70 patients with liver cirrhosis (Child B and C&#xD;
      stages up to 10 points) who were randomized to receive enoxaparin for a year (n = 34) vs no&#xD;
      intervention (n = 36) showed that anticoagulant treatment with enoxaparin is safe and&#xD;
      effective, significantly reducing risk of PVT development and liver decompensation, markedly&#xD;
      improving overall survival. This study provides exciting preliminary data regarding the&#xD;
      potential use of prophylactic anticoagulation in improving clinical outcomes in cirrhosis,&#xD;
      beyond the prevention of portal vein thrombosis. This study suggested that the effect was&#xD;
      partly due to a direct effect of reducing BT and levels of proinflammatory cytokines.&#xD;
      However, this study included few patients, was not double blind, and did not have a placebo&#xD;
      group. Therefore, despite the spectacular results, the use of prophylactic anticoagulant&#xD;
      therapy has not become routine practice in patients with cirrhosis and more studies are&#xD;
      needed to assess the potential usefulness of anticoagulation in improving the prognosis of&#xD;
      liver cirrhosis.&#xD;
&#xD;
      Transjugular intrahepatic portosystemic shunts (TIPS) are now routinely used to treat the&#xD;
      complications of portal hypertension, such as variceal bleeding and refractory ascites. TIPS&#xD;
      is the most effective method to prevent rebleeding, however, it is burdened with increased&#xD;
      risk of hepatic encephalopathy and deterioration of liver function in patients with advanced&#xD;
      cirrhosis. Notably, TIPS can not only relieve portal pressure but also can redirect the&#xD;
      portal blood flow through the shunt directly into the systemic circulation which can cause&#xD;
      systemic hemodynamic changes.&#xD;
&#xD;
      Given the preliminary data suggesting a beneficial effect of prophylactic anticoagulation&#xD;
      with LMWH in cirrhotic patients, this multicenter randomized controlled study attempts to&#xD;
      demonstrate the effect of long term LMWH therapy after TIPS on survival in cirrhotic patients&#xD;
      with variceal bleeding.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 14, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>N/A</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Transplant-free survival</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with all-cause rebleeding</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with overt hepatic encephalopathy</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with recurrent or worsening ascites</measure>
    <time_frame>2 years</time_frame>
    <description>Perform two or more evacuative paracentesis in the following six months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with shunt dysfunction</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of anticoagulation on liver function estimated by the Child-Pugh and the model for end-stage liver disease scores</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Echocardiography findings</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of bacterial translocation biomarkers and proinflammatory cytokines</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Security of anticoagulation in patients with liver cirrhosis</measure>
    <time_frame>2 years</time_frame>
    <description>Number of adverse events and adverse reactions in each arm of study. History and clinical evaluation of bleeding and monitoring of hematocrit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compliance</measure>
    <time_frame>2 years</time_frame>
    <description>Record of unused packaging and information about compliance in a patient diary</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Score of Health Related Quality of Life questionnaire，for example, SF-36</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">254</enrollment>
  <condition>Liver Cirrhosis</condition>
  <arm_group>
    <arm_group_label>Anticoagulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rivaroxaban：10mg/d for 2 years</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-anticoagulated</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No anticoagulants will be used.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rivaroxaban</intervention_name>
    <description>10mg/day, for 2 years</description>
    <arm_group_label>Anticoagulation</arm_group_label>
    <other_name>Nadroparin or Enoxaparin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        All inclusion criteria must be met at the time of screening:&#xD;
&#xD;
          -  Signed informed consent.&#xD;
&#xD;
          -  Male or female patients with an age of 18 to 75 years&#xD;
&#xD;
          -  Liver cirrhosis.&#xD;
&#xD;
          -  History of variceal bleeding &gt; 5 days&#xD;
&#xD;
          -  Presence of ascites&#xD;
&#xD;
          -  Successful TIPS&#xD;
&#xD;
          -  Use of Viatorr stent&#xD;
&#xD;
          -  Child-Pugh score within B7-C13&#xD;
&#xD;
          -  Bilirubin level of 3 mg/dL or less (51.3 umol/L)&#xD;
&#xD;
        Patients who meet the following criteria at the time of screening will be excluded:&#xD;
&#xD;
          -  Hepatocellular carcinoma or other intrahepatic/extrahepatic cancers.&#xD;
&#xD;
          -  Spontaneous overt hepatic encephalopathy.&#xD;
&#xD;
          -  Previous or current portal venous system thrombosis.&#xD;
&#xD;
          -  Budd-Chiari syndrome.&#xD;
&#xD;
          -  Known coagulation disorder besides liver cirrhosis.&#xD;
&#xD;
          -  Severe thrombocytopenia &lt;15,000 platelets/dl.&#xD;
&#xD;
          -  Peptic ulcer disease in the last 6 months.&#xD;
&#xD;
          -  Unstable angina or myocardial infarction (MI) within the past 6 months before&#xD;
             randomization.&#xD;
&#xD;
          -  Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are&#xD;
             permitted).&#xD;
&#xD;
          -  Uncontrolled hypertension.&#xD;
&#xD;
          -  Prior liver transplantation or candidates for liver transplantation.&#xD;
&#xD;
          -  History of shunting surgery or TIPS before randomization.&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Poor compliance&#xD;
&#xD;
          -  Participation in another clinical trial&#xD;
&#xD;
          -  Close affiliation with the investigational site.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Guohong Han, MD,Ph.D</last_name>
    <phone>+86-13991969930</phone>
    <email>13991969930@126.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>The Third Affiliated Hospital of Sun Yat-sen University</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Nanfang Hospital Affiliated to Southern Medical University</name>
      <address>
        <city>Guanzhou</city>
        <state>Guangdong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The first affiliated hospital of Nanchang university</name>
      <address>
        <city>Nanchang</city>
        <state>Jiangxi</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital, Air Force Medical University</name>
      <address>
        <city>Xi'an</city>
        <state>Shaanxi</state>
        <zip>710032</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Xi'an International Medical Center Hospital</name>
      <address>
        <city>Xi'an</city>
        <state>Shaanxi</state>
        <zip>710100</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Guohong Han, MD,Ph.D</last_name>
      <email>13991969930@126.com</email>
    </contact>
    <investigator>
      <last_name>Guohong Han, MD,Ph.D</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Hui Chen, MD,Ph.D</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Xi'an Jiaotong University</name>
      <address>
        <city>Xi'an</city>
        <state>Shaanxi</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Provincial Hospital Affiliated to Shandong University</name>
      <address>
        <city>Jinan</city>
        <state>Shandong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Xinjiang Medical University</name>
      <address>
        <city>Ürümqi</city>
        <state>Xinjiang</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The Second Affiliated Hospital of Kunming Medical University</name>
      <address>
        <city>Kunming</city>
        <state>Yunnan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Zhejiang University</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 24, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 29, 2016</study_first_posted>
  <last_update_submitted>October 22, 2022</last_update_submitted>
  <last_update_submitted_qc>October 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Xi'an International Medical Center Hospital</investigator_affiliation>
    <investigator_full_name>Guohong Han</investigator_full_name>
    <investigator_title>MD，PhD，Professor</investigator_title>
  </responsible_party>
  <keyword>liver cirrhosis</keyword>
  <keyword>Transjugular Intrahepatic Portosystemic Stent Shunt</keyword>
  <keyword>Anticoagulation</keyword>
  <keyword>Survival</keyword>
  <keyword>Additional decompensation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Nadroparin</mesh_term>
    <mesh_term>Rivaroxaban</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/NCT03005444
org study id: APPROACH
nct id: NCT03005444
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recent studies demonstrated that liver cirrhosis was associated with a hypercoagulability
      state. Besides, bacterial translocation plays an important role in the pathogenesis and
      complications in patients with decompensated cirrhosis, including infections as well as
      hepatic encephalopathy and hepatorenal syndrome.

      A recent prospective study in a group of 70 patients with liver cirrhosis (Child B and C
      stages up to 10 points) who were randomized to receive enoxaparin for a year (n = 34) vs no
      intervention (n = 36) showed that anticoagulant treatment with enoxaparin is safe and
      effective, significantly reducing risk of PVT development and liver decompensation, markedly
      improving overall survival. This study provides exciting preliminary data regarding the
      potential use of prophylactic anticoagulation in improving clinical outcomes in cirrhosis,
      beyond the prevention of portal vein thrombosis. This study suggested that the effect was
      partly due to a direct effect of reducing BT and levels of proinflammatory cytokines.
      However, this study included few patients, was not double blind, and did not have a placebo
      group. Therefore, despite the spectacular results, the use of prophylactic anticoagulant
      therapy has not become routine practice in patients with cirrhosis and more studies are
      needed to assess the potential usefulness of anticoagulation in improving the prognosis of
      liver cirrhosis.

      Transjugular intrahepatic portosystemic shunts (TIPS) are now routinely used to treat the
      complications of portal hypertension, such as variceal bleeding and refractory ascites. TIPS
      is the most effective method to prevent rebleeding, however, it is burdened with increased
      risk of hepatic encephalopathy and deterioration of liver function in patients with advanced
      cirrhosis. Notably, TIPS can not only relieve portal pressure but also can redirect the
      portal blood flow through the shunt directly into the systemic circulation which can cause
      systemic hemodynamic changes.

      Given the preliminary data suggesting a beneficial effect of prophylactic anticoagulation
      with LMWH in cirrhotic patients, this multicenter randomized controlled study attempts to
      demonstrate the effect of long term LMWH therapy after TIPS on survival in cirrhotic patients
      with variceal bleeding.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Transplant-free survival
time frame: 2 years
measure: Number of participants with all-cause rebleeding
time frame: 2 years
measure: Number of participants with overt hepatic encephalopathy
time frame: 2 years
measure: Number of participants with recurrent or worsening ascites
time frame: 2 years
description: Perform two or more evacuative paracentesis in the following six months
measure: Number of participants with shunt dysfunction
time frame: 2 years
measure: Effect of anticoagulation on liver function estimated by the Child-Pugh and the model for end-stage liver disease scores
time frame: 2 years
measure: Echocardiography findings
time frame: 2 years
measure: Serum levels of bacterial translocation biomarkers and proinflammatory cytokines
time frame: 2 years
measure: Security of anticoagulation in patients with liver cirrhosis
time frame: 2 years
description: Number of adverse events and adverse reactions in each arm of study. History and clinical evaluation of bleeding and monitoring of hematocrit.
measure: Compliance
time frame: 2 years
description: Record of unused packaging and information about compliance in a patient diary
measure: Score of Health Related Quality of Life questionnaire，for example, SF-36
time frame: 2 years
arm group label: Anticoagulation
arm group type: Experimental
description: Rivaroxaban：10mg/d for 2 years
arm group label: Non-anticoagulated
arm group type: No Intervention
description: No anticoagulants will be used.
intervention type: Drug
intervention name: Rivaroxaban
description: 10mg/day, for 2 years
arm group label: Anticoagulation
other name: Nadroparin or Enoxaparin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Guohong Han, MD,Ph.D
phone: +86-13991969930
email: 13991969930@126.com
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Completed
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
country: China
responsible party type: Principal Investigator
investigator affiliation: Xi'an International Medical Center Hospital
investigator full name: Guohong Han
investigator title: MD，PhD，Professor
mesh term: Liver Cirrhosis
mesh term: Fibrosis
mesh term: Enoxaparin
mesh term: Nadroparin
mesh term: Rivaroxaban