<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/NCT01716611</url>
  </required_header>
  <id_info>
    <org_study_id>KUH1010412</org_study_id>
    <nct_id>NCT01716611</nct_id>
  </id_info>
  <brief_title>Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites</brief_title>
  <acronym>TONIC</acronym>
  <official_title>Efficacy and Safety Study of Tolvaptan for Liver Cirrhotic Patients With Hyponatremia and Ascites: A Multi-center, Randomized, Double-blind, Placebo-controlled 4-weeks Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Konkuk University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Inje University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Korea University Anam Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hanyang University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Severance Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Seoul St. Mary's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Samsung Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chung-Ang University Hosptial, Chung-Ang University College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hallym University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Inha University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Soonchunhyang University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kyungpook National University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Incheon St.Mary's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chungnam National University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Konkuk University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to investigate the efficacy and safety for the management of&#xD;
      hyponatremia and ascites in patients with liver cirrhosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with advanced cirrhosis frequently develop dilutional hyponatremia due to impairment&#xD;
      of their renal ability to eliminate solute-free water. Although the pathophysiology of this&#xD;
      disorder is multifactorial, an increased hypersecretion of arginine vasopressin (AVP) is a&#xD;
      major factor. The prevalence of hyponatremia in cirrhosis, as defined by a serum sodium level&#xD;
      of 130 mmol/L is reported to be about 20%, and there are several lines of evidence that&#xD;
      hyponatremia is a risk factor for the development of hepatic encephalopathy, and that it&#xD;
      predicts a poor quality of life independent of liver function. Hyponatremia also predicts&#xD;
      short-term mortality in cirrhotic patients awaiting liver transplantation. The principle of&#xD;
      the management of hypervolemic hypona- tremia is to induce a negative water balance, with the&#xD;
      aim of normalizing the increased total body water, which would result in an improvement in&#xD;
      serum sodium concentration. Fluid restriction is the most widely accepted nonpharmacological&#xD;
      therapy, but its efficacy is very limited. The administration of hypertonic sodium chloride&#xD;
      has been common in severe hypervolemic hyponatremia, but its effect is only partial and short&#xD;
      lived; moreover, additional expansion of fluid can worsen ascites and edema. Therefore, the&#xD;
      pathophysiologically oriented treatment of hyponatremia focuses on inhibiting the actions of&#xD;
      AVP. Recently, antagonists of the V2 receptors of vasopressin has been proposed to manage&#xD;
      hyponatremic patients, such as heart fauilure, syndrome of inappropriate antidiuretic hormone&#xD;
      or liver cirrhosis. Especially, a lot of hyponatremic patients with cirrhosis had ascites,&#xD;
      and some of them had intractable ascites. In these patients, antagonists of the V2 receptors&#xD;
      of vasopressin including tolvaptan might have beneficial effect in enhancing not only&#xD;
      hyponatremia , but also ascites&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>November 2012</start_date>
  <completion_date type="Anticipated">February 2014</completion_date>
  <primary_completion_date type="Anticipated">January 2014</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention</measure>
    <time_frame>baseline and 28 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4</measure>
    <time_frame>baseline and 4 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the time to normalization of the serum sodium concentration</measure>
    <time_frame>up to 28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis</measure>
    <time_frame>up to 28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abdominal discomfort based on a 100-mm visual analogue scales (VAS)</measure>
    <time_frame>day 1, 2, 3, 4, 7, 14, 21, 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The change in the dose of concomitant diuretics from baseline at day 28</measure>
    <time_frame>day 1, 2, 3, 4, 7, 14, 21, 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the number of participants with serious adverse events</measure>
    <time_frame>from baseline to day 28 after intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the time to ascites improvement</measure>
    <time_frame>up to 28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the time of worsening of ascites</measure>
    <time_frame>up to 28 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">105</enrollment>
  <condition>Hyponatremia</condition>
  <condition>Ascites</condition>
  <arm_group>
    <arm_group_label>Tolvaptan group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolvaptan</intervention_name>
    <description>15 - 60 mg/day for 28 days</description>
    <arm_group_label>Tolvaptan group</arm_group_label>
    <other_name>SAMSCA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 20 years of age or older&#xD;
&#xD;
          2. Patients with cirrhosis as diagnosed by liver biopsy or a combination of laboratory&#xD;
             (thrombocytopenia), radiologic (cirrhotic feature of liver, splenomegaly, collateral&#xD;
             shunt on US, CT, or MRI) and endoscopic findings (gastoesophageal varices or portal&#xD;
             hypertensive gastropathy)&#xD;
&#xD;
          3. ≥ Grade 2 ascites who have already been treated with restricted salt diet within 3&#xD;
             month&#xD;
&#xD;
          4. Hyponatremia (Serum sodium ≥120 mEq/L and ≤130 mEq/L)&#xD;
&#xD;
          5. Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hypovolemic hyponatremia (Patients with hypotension or chronic heart failure)&#xD;
&#xD;
          2. Serum potassium concentration &gt; 5.5 mEq/L&#xD;
&#xD;
          3. Serum bilirubin &gt; 5.0 mg/dL&#xD;
&#xD;
          4. Blood coagulation factor &lt; 40% or international normalized ratio (INR) &gt; 2.3&#xD;
&#xD;
          5. Platelet count &lt; 30,000/mm3&#xD;
&#xD;
          6. Serum creatinine &gt; 3 mg/dL&#xD;
&#xD;
          7. Treatment within 2 weeks with vasopressin anlogues&#xD;
&#xD;
          8. Systolic blood pressure &lt;80 mmHg&#xD;
&#xD;
          9. History of gastrointestinalesophageal varix bleeding variceal hemorrhage&#xD;
&#xD;
         10. Spontaneous bacterial peritonitis&#xD;
&#xD;
         11. Hepatic encephalopathy ≥ grade 3&#xD;
&#xD;
         12. History of Hepatocellular carcinoma treatment within 3month or viable tumor Viable&#xD;
             hepatocellular carcinoma&#xD;
&#xD;
         13. Liver transplant&#xD;
&#xD;
         14. Previous treatment with transjugular intrahepatic portosystemic stent shunt (TIPS)&#xD;
&#xD;
         15. History of significant cardiac diseases such as recent myocardial infarction or&#xD;
             ischemic diseases within 1 year of screening&#xD;
&#xD;
         16. Prolonged QTc interval of &gt; 500 ms based on electrocardiography&#xD;
&#xD;
         17. Treatment within 2 weeks with substances or drugs that may either induce or&#xD;
             significantly inhibit cytochrome P450 3A (ketoconazole, clarithromycin, erythromycin,&#xD;
             fluconazole, diltiazem, verapamil, etc)&#xD;
&#xD;
         18. Pregnant or breast feeding&#xD;
&#xD;
         19. Patients with galactose intolerance or malabsorption (as production of the drug&#xD;
             contains lactose)&#xD;
&#xD;
         20. HbA1Cc ≥ 9 %&#xD;
&#xD;
         21. Serious medical illness (e.g. heart failure, severe pulmonary disorders, alcohol&#xD;
             dependence, malignant tumors, etc)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>June Sung Lee, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inje University Ilsan Paik Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Won Hyeok Choe, MD</last_name>
    <phone>82-2-2030-7506</phone>
    <email>20050101@kuh.ac.kr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Konkuk University Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>143-729</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <contact>
      <last_name>Won Hyeok Choe, MD</last_name>
      <phone>82-2-2030-5027</phone>
      <email>20050101@kuh.ac.kr</email>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>October 2012</verification_date>
  <study_first_submitted>October 18, 2012</study_first_submitted>
  <study_first_submitted_qc>October 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 30, 2012</study_first_posted>
  <last_update_submitted>October 29, 2012</last_update_submitted>
  <last_update_submitted_qc>October 29, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 30, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Konkuk University Medical Center</investigator_affiliation>
    <investigator_full_name>Won Hyeok Choe</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>liver cirrhosis</keyword>
  <keyword>hyponatemia</keyword>
  <keyword>ascites</keyword>
  <keyword>vaptans</keyword>
  <keyword>antidiuretic hormon</keyword>
  <keyword>arginine vasopressin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyponatremia</mesh_term>
    <mesh_term>Ascites</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tolvaptan</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/NCT01716611
org study id: KUH1010412
nct id: NCT01716611
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of the study is to investigate the efficacy and safety for the management of
      hyponatremia and ascites in patients with liver cirrhosis.
Patients with advanced cirrhosis frequently develop dilutional hyponatremia due to impairment
      of their renal ability to eliminate solute-free water. Although the pathophysiology of this
      disorder is multifactorial, an increased hypersecretion of arginine vasopressin (AVP) is a
      major factor. The prevalence of hyponatremia in cirrhosis, as defined by a serum sodium level
      of 130 mmol/L is reported to be about 20%, and there are several lines of evidence that
      hyponatremia is a risk factor for the development of hepatic encephalopathy, and that it
      predicts a poor quality of life independent of liver function. Hyponatremia also predicts
      short-term mortality in cirrhotic patients awaiting liver transplantation. The principle of
      the management of hypervolemic hypona- tremia is to induce a negative water balance, with the
      aim of normalizing the increased total body water, which would result in an improvement in
      serum sodium concentration. Fluid restriction is the most widely accepted nonpharmacological
      therapy, but its efficacy is very limited. The administration of hypertonic sodium chloride
      has been common in severe hypervolemic hyponatremia, but its effect is only partial and short
      lived; moreover, additional expansion of fluid can worsen ascites and edema. Therefore, the
      pathophysiologically oriented treatment of hyponatremia focuses on inhibiting the actions of
      AVP. Recently, antagonists of the V2 receptors of vasopressin has been proposed to manage
      hyponatremic patients, such as heart fauilure, syndrome of inappropriate antidiuretic hormone
      or liver cirrhosis. Especially, a lot of hyponatremic patients with cirrhosis had ascites,
      and some of them had intractable ascites. In these patients, antagonists of the V2 receptors
      of vasopressin including tolvaptan might have beneficial effect in enhancing not only
      hyponatremia , but also ascites
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention
time frame: baseline and 28 days
measure: the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4
time frame: baseline and 4 days
measure: the time to normalization of the serum sodium concentration
time frame: up to 28 days
measure: the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis
time frame: up to 28 days
measure: Abdominal discomfort based on a 100-mm visual analogue scales (VAS)
time frame: day 1, 2, 3, 4, 7, 14, 21, 28
measure: The change in the dose of concomitant diuretics from baseline at day 28
time frame: day 1, 2, 3, 4, 7, 14, 21, 28
measure: the number of participants with serious adverse events
time frame: from baseline to day 28 after intervention
measure: the time to ascites improvement
time frame: up to 28 days
measure: the time of worsening of ascites
time frame: up to 28 days
arm group label: Tolvaptan group
arm group type: Active Comparator
description: Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
arm group label: Placebo group
arm group type: Placebo Comparator
description: Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
intervention type: Drug
intervention name: Tolvaptan
description: 15 - 60 mg/day for 28 days
arm group label: Tolvaptan group
other name: SAMSCA
intervention type: Drug
intervention name: placebo
arm group label: Placebo group
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: June Sung Lee, MD, PhD
role: Principal Investigator
affiliation: Inje University Ilsan Paik Hospital
last name: Won Hyeok Choe, MD
phone: 82-2-2030-7506
email: 20050101@kuh.ac.kr
facility: 
contact: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Konkuk University Medical Center
investigator full name: Won Hyeok Choe
investigator title: Associate Professor
mesh term: Hyponatremia
mesh term: Ascites
mesh term: Tolvaptan