Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites

Hyponatremia Clinical Trial

— TONIC  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01716611
• Other study ID #: KUH1010412
• Status: Not yet recruiting
• Phase: Phase 4
• First received: October 18, 2012
• Last updated: October 29, 2012
• Start date: November 2012
• Est. completion date: February 2014

Study information

• Verified date: October 2012
• Source: Konkuk University Medical Center
• Contact: Won Hyeok Choe, MD
• Phone: 82-2-2030-7506
• Email: 20050101[@]kuh.ac.kr
• Is FDA regulated: No
• Health authority: Korea: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 105
• Est. completion date: February 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ascites
• Hyponatremia

Intervention

Drug:
• Tolvaptan
15 - 60 mg/day for 28 days
• placebo

Locations

Country	Name	City	State
Korea, Republic of	Konkuk University Medical Center	Seoul

Sponsors (14)

Lead Sponsor	Collaborator
Konkuk University Medical Center	Chung-Ang University Hospital, Chungnam National University, Hallym University Medical Center, Hanyang University, Incheon St.Mary's Hospital, Inha University Hospital, Inje University, Korea University Anam Hospital, Kyungpook National University, Samsung Medical Center, Seoul St. Mary's Hospital, Severance Hospital, Soonchunhyang University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

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