Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites (TONIC)

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

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

Study Overview

• Status: Unknown
• Conditions: Ascites; Hyponatremia
• Intervention / Treatment: Drug: placebo; Drug: Tolvaptan

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 Type: Interventional
• Enrollment (Anticipated): 105
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 143-729
    • Konkuk University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: SAMSCA
PLACEBO_COMPARATOR: Placebo group; Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days	Drug: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention	baseline and 28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4	baseline and 4 days
the time to normalization of the serum sodium concentration	up to 28 days
the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis	up to 28 days
Abdominal discomfort based on a 100-mm visual analogue scales (VAS)	day 1, 2, 3, 4, 7, 14, 21, 28
The change in the dose of concomitant diuretics from baseline at day 28	day 1, 2, 3, 4, 7, 14, 21, 28
the number of participants with serious adverse events	from baseline to day 28 after intervention
the time to ascites improvement	up to 28 days
the time of worsening of ascites	up to 28 days

Collaborators and Investigators

• Sponsor: Konkuk University Medical Center
• Collaborators: Samsung Medical Center; Seoul St. Mary's Hospital; Korea University Anam Hospital; Kyungpook National University Hospital; Chung-Ang University Hosptial, Chung-Ang University College of Medicine; Inje University; Hanyang University; Severance Hospital; Soonchunhyang University Hospital; Hallym University Medical Center; Incheon St.Mary's Hospital; Inha University Hospital; Chungnam National University
• Investigators: Principal Investigator: June Sung Lee, MD, PhD, Inje University Ilsan Paik Hospital

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ANTICIPATED): January 1, 2014
• Study Completion (ANTICIPATED): February 1, 2014

Study Registration Dates

• First Submitted: October 18, 2012
• First Submitted That Met QC Criteria: October 29, 2012
• First Posted (ESTIMATE): October 30, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): October 30, 2012
• Last Update Submitted That Met QC Criteria: October 29, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: liver cirrhosis; ascites; arginine vasopressin; hyponatemia; vaptans; antidiuretic hormon
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Water-Electrolyte Imbalance; Ascites; Hyponatremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: KUH1010412