Clinical trial NCT01716611: Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hyponatremia
Ascites
Keywords: liver cirrhosis
hyponatemia
ascites
vaptans
antidiuretic hormon
arginine vasopressin
Lead sponsor: Konkuk University Medical Center
Sponsor class: OTHER
Collaborators: name: Inje University
name: Korea University Anam Hospital
name: Hanyang University
name: Severance Hospital
name: Seoul St. Mary's Hospital
name: Samsung Medical Center
name: Chung-Ang University Hosptial, Chung-Ang University College of Medicine
name: Hallym University Medical Center
name: Inha University Hospital
name: Soonchunhyang University Hospital
name: Kyungpook National University Hospital
name: Incheon St.Mary's Hospital
name: Chungnam National University
First posted: 2012-10-30
Enrollment: 105
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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)

Primary outcomes:
measure: the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention
timeFrame: baseline and 28 days
Secondary outcomes:
measure: the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4
timeFrame: baseline and 4 days
measure: the time to normalization of the serum sodium concentration
timeFrame: up to 28 days
measure: the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis
timeFrame: up to 28 days
measure: Abdominal discomfort based on a 100-mm visual analogue scales (VAS)
timeFrame: day 1, 2, 3, 4, 7, 14, 21, 28
measure: The change in the dose of concomitant diuretics from baseline at day 28
timeFrame: day 1, 2, 3, 4, 7, 14, 21, 28
measure: the number of participants with serious adverse events
timeFrame: from baseline to day 28 after intervention
measure: the time to ascites improvement
timeFrame: up to 28 days
measure: the time of worsening of ascites
timeFrame: up to 28 days
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
Study officials:
affiliation: Inje University Ilsan Paik Hospital
name: June Sung Lee, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: