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Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites (TONIC)

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ClinicalTrials.gov Identifier: NCT01716611
Recruitment Status : Unknown
Verified October 2012 by Won Hyeok Choe, Konkuk University Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : October 30, 2012
Last Update Posted : October 30, 2012
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of the study is to investigate the efficacy and safety for the management of hyponatremia and ascites in patients with liver cirrhosis.

Condition or disease Intervention/treatment Phase
Hyponatremia Ascites Drug: Tolvaptan Drug: placebo Phase 4

Detailed Description:
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

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Study Start Date : November 2012
Estimated Primary Completion Date : January 2014
Estimated Study Completion Date : February 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Tolvaptan
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Active Comparator: Tolvaptan group
Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
Drug: Tolvaptan
15 - 60 mg/day for 28 days
Other Name: SAMSCA
Placebo Comparator: Placebo group
Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
Drug: placebo

Outcome Measures

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. the time to normalization of the serum sodium concentration [ Time Frame: up to 28 days ]
  3. the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis [ Time Frame: up to 28 days ]
  4. Abdominal discomfort based on a 100-mm visual analogue scales (VAS) [ Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28 ]
  5. The change in the dose of concomitant diuretics from baseline at day 28 [ Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28 ]
  6. the number of participants with serious adverse events [ Time Frame: from baseline to day 28 after intervention ]
  7. the time to ascites improvement [ Time Frame: up to 28 days ]
  8. the time of worsening of ascites [ Time Frame: up to 28 days ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 20 years of age or older
  2. Patients with cirrhosis as diagnosed by liver biopsy or a combination of laboratory (thrombocytopenia), radiologic (cirrhotic feature of liver, splenomegaly, collateral shunt on US, CT, or MRI) and endoscopic findings (gastoesophageal varices or portal hypertensive gastropathy)
  3. ≥ Grade 2 ascites who have already been treated with restricted salt diet within 3 month
  4. Hyponatremia (Serum sodium ≥120 mEq/L and ≤130 mEq/L)
  5. Written informed consent

Exclusion Criteria:

  1. Hypovolemic hyponatremia (Patients with hypotension or chronic heart failure)
  2. Serum potassium concentration > 5.5 mEq/L
  3. Serum bilirubin > 5.0 mg/dL
  4. Blood coagulation factor < 40% or international normalized ratio (INR) > 2.3
  5. Platelet count < 30,000/mm3
  6. Serum creatinine > 3 mg/dL
  7. Treatment within 2 weeks with vasopressin anlogues
  8. Systolic blood pressure <80 mmHg
  9. History of gastrointestinalesophageal varix bleeding variceal hemorrhage
  10. Spontaneous bacterial peritonitis
  11. Hepatic encephalopathy ≥ grade 3
  12. History of Hepatocellular carcinoma treatment within 3month or viable tumor Viable hepatocellular carcinoma
  13. Liver transplant
  14. Previous treatment with transjugular intrahepatic portosystemic stent shunt (TIPS)
  15. History of significant cardiac diseases such as recent myocardial infarction or ischemic diseases within 1 year of screening
  16. Prolonged QTc interval of > 500 ms based on electrocardiography
  17. Treatment within 2 weeks with substances or drugs that may either induce or significantly inhibit cytochrome P450 3A (ketoconazole, clarithromycin, erythromycin, fluconazole, diltiazem, verapamil, etc)
  18. Pregnant or breast feeding
  19. Patients with galactose intolerance or malabsorption (as production of the drug contains lactose)
  20. HbA1Cc ≥ 9 %
  21. Serious medical illness (e.g. heart failure, severe pulmonary disorders, alcohol dependence, malignant tumors, etc)
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01716611

Contact: Won Hyeok Choe, MD 82-2-2030-7506 20050101@kuh.ac.kr

Korea, Republic of
Konkuk University Medical Center Not yet recruiting
Seoul, Korea, Republic of, 143-729
Contact: Won Hyeok Choe, MD    82-2-2030-5027    20050101@kuh.ac.kr   
Sponsors and Collaborators
Konkuk University Medical Center
Inje University
Korea University Anam Hospital
Hanyang University
Severance Hospital
Seoul St. Mary's Hospital
Samsung Medical Center
Chung-Ang University Hosptial, Chung-Ang University College of Medicine
Hallym University Medical Center
Inha University Hospital
Soonchunhyang University Hospital
Kyungpook National University
Incheon St.Mary's Hospital
Chungnam National University
Principal Investigator: June Sung Lee, MD, PhD Inje University
More Information

Responsible Party: Won Hyeok Choe, Associate Professor, Konkuk University Medical Center
ClinicalTrials.gov Identifier: NCT01716611     History of Changes
Other Study ID Numbers: KUH1010412
First Posted: October 30, 2012    Key Record Dates
Last Update Posted: October 30, 2012
Last Verified: October 2012

Keywords provided by Won Hyeok Choe, Konkuk University Medical Center:
liver cirrhosis
antidiuretic hormon
arginine vasopressin

Additional relevant MeSH terms:
Pathologic Processes
Water-Electrolyte Imbalance
Metabolic Diseases
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs