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Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites (TONIC)

This study is not yet open for participant recruitment.
Verified October 2012 by Konkuk University Medical Center
Sponsor:
Collaborators:
Inje University
Korea University Anam Hospital
Hanyang University
Severance Hospital
Seoul St. Mary's Hospital
Samsung Medical Center
Chung-Ang University Hospital
Hallym University Medical Center
Inha University Hospital
Soonchunhyang University Hospital
Kyungpook National University
Incheon St.Mary's Hospital
Chungnam National University
Information provided by (Responsible Party):
Won Hyeok Choe, Konkuk University Medical Center
ClinicalTrials.gov Identifier:
NCT01716611
First received: October 18, 2012
Last updated: October 29, 2012
Last verified: October 2012
History of Changes
  Purpose

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 Intervention Phase
Hyponatremia
Ascites
 Drug: Tolvaptan
Drug: placebo
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:

MedlinePlus related topics: Cirrhosis
Drug Information available for: Tolvaptan
U.S. FDA Resources

Further study details as provided by Konkuk University Medical Center:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • the time to normalization of the serum sodium concentration [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]
  • the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]
  • Abdominal discomfort based on a 100-mm visual analogue scales (VAS) [ Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28 ] [ Designated as safety issue: No ]
  • The change in the dose of concomitant diuretics from baseline at day 28 [ Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28 ] [ Designated as safety issue: No ]
  • the number of participants with serious adverse events [ Time Frame: from baseline to day 28 after intervention ] [ Designated as safety issue: Yes ]
  • the time to ascites improvement [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]
  • the time of worsening of ascites [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 105
Study Start Date: November 2012
Estimated Study Completion Date: February 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01716611

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

Locations
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 Hospital
Hallym University Medical Center
Inha University Hospital
Soonchunhyang University Hospital
Kyungpook National University
Incheon St.Mary's Hospital
Chungnam National University
Investigators
Principal Investigator: June Sung Lee, MD, PhD Inje University
  More Information

No publications provided

Responsible Party: Won Hyeok Choe, Associate Professor, Konkuk University Medical Center
ClinicalTrials.gov Identifier: NCT01716611     History of Changes
Other Study ID Numbers: KUH1010412
Study First Received: October 18, 2012
Last Updated: October 29, 2012
Health Authority: Korea: Institutional Review Board

Keywords provided by Konkuk University Medical Center:
liver cirrhosis
hyponatemia
ascites
 vaptans
antidiuretic hormon
arginine vasopressin

Additional relevant MeSH terms:
Ascites
Hyponatremia
Pathologic Processes
Water-Electrolyte Imbalance
Metabolic Diseases

ClinicalTrials.gov processed this record on May 23, 2013