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Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites (TONIC)

Primary Purpose

Hyponatremia, Ascites

Status

Unknown status

Phase

Phase 4

Locations

Korea, Republic of

Study Type

Interventional

Intervention

Tolvaptan

placebo

About this trial

This is an interventional treatment trial for Hyponatremia focused on measuring liver cirrhosis, hyponatemia, ascites, vaptans, antidiuretic hormon, arginine vasopressin

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

20 years of age or older
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)
≥ Grade 2 ascites who have already been treated with restricted salt diet within 3 month
Hyponatremia (Serum sodium ≥120 mEq/L and ≤130 mEq/L)
Written informed consent

Exclusion Criteria:

Hypovolemic hyponatremia (Patients with hypotension or chronic heart failure)
Serum potassium concentration > 5.5 mEq/L
Serum bilirubin > 5.0 mg/dL
Blood coagulation factor < 40% or international normalized ratio (INR) > 2.3
Platelet count < 30,000/mm3
Serum creatinine > 3 mg/dL
Treatment within 2 weeks with vasopressin anlogues
Systolic blood pressure <80 mmHg
History of gastrointestinalesophageal varix bleeding variceal hemorrhage
Spontaneous bacterial peritonitis
Hepatic encephalopathy ≥ grade 3
History of Hepatocellular carcinoma treatment within 3month or viable tumor Viable hepatocellular carcinoma
Liver transplant
Previous treatment with transjugular intrahepatic portosystemic stent shunt (TIPS)
History of significant cardiac diseases such as recent myocardial infarction or ischemic diseases within 1 year of screening
Prolonged QTc interval of > 500 ms based on electrocardiography
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)
Pregnant or breast feeding
Patients with galactose intolerance or malabsorption (as production of the drug contains lactose)
HbA1Cc ≥ 9 %
Serious medical illness (e.g. heart failure, severe pulmonary disorders, alcohol dependence, malignant tumors, etc)

Sites / Locations

Konkuk University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Tolvaptan group

Placebo group

Arm Description

Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days

Outcomes

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

Secondary Outcome Measures

the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4

the time to normalization of the serum sodium concentration

the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis

Abdominal discomfort based on a 100-mm visual analogue scales (VAS)

The change in the dose of concomitant diuretics from baseline at day 28

the number of participants with serious adverse events

the time to ascites improvement

the time of worsening of ascites

Full Information

NCT ID

NCT01716611

First Posted

October 18, 2012

Last Updated

October 29, 2012

Sponsor

Konkuk University Medical Center

Collaborators

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 Hospital, Incheon St.Mary's Hospital, Chungnam National University

1. Study Identification

Unique Protocol Identification Number

NCT01716611

Brief Title

Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2012

Overall Recruitment Status

Unknown status

Study Start Date

November 2012 (undefined)

Primary Completion Date

January 2014 (Anticipated)

Study Completion Date

February 2014 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Konkuk University Medical Center

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyponatremia, Ascites

Keywords

liver cirrhosis, hyponatemia, ascites, vaptans, antidiuretic hormon, arginine vasopressin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

105 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Tolvaptan group

Arm Type

Active Comparator

Arm Description

Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days

Arm Title

Placebo group

Arm Type

Placebo Comparator

Arm Description

Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days

Intervention Type

Drug

Intervention Name(s)

Tolvaptan

Other Intervention Name(s)

SAMSCA

Intervention Description

15 - 60 mg/day for 28 days

Intervention Type

Drug

Intervention Name(s)

placebo

Primary Outcome Measure Information:

Title

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 Measure Information:

Title

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

Title

the time to normalization of the serum sodium concentration

Time Frame

up to 28 days

Title

the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis

Time Frame

up to 28 days

Title

Abdominal discomfort based on a 100-mm visual analogue scales (VAS)

Time Frame

day 1, 2, 3, 4, 7, 14, 21, 28

Title

The change in the dose of concomitant diuretics from baseline at day 28

Time Frame

day 1, 2, 3, 4, 7, 14, 21, 28

Title

the number of participants with serious adverse events

Time Frame

from baseline to day 28 after intervention

Title

the time to ascites improvement

Time Frame

up to 28 days

Title

the time of worsening of ascites

Time Frame

up to 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 20 years of age or older 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) ≥ Grade 2 ascites who have already been treated with restricted salt diet within 3 month Hyponatremia (Serum sodium ≥120 mEq/L and ≤130 mEq/L) Written informed consent Exclusion Criteria: Hypovolemic hyponatremia (Patients with hypotension or chronic heart failure) Serum potassium concentration > 5.5 mEq/L Serum bilirubin > 5.0 mg/dL Blood coagulation factor < 40% or international normalized ratio (INR) > 2.3 Platelet count < 30,000/mm3 Serum creatinine > 3 mg/dL Treatment within 2 weeks with vasopressin anlogues Systolic blood pressure <80 mmHg History of gastrointestinalesophageal varix bleeding variceal hemorrhage Spontaneous bacterial peritonitis Hepatic encephalopathy ≥ grade 3 History of Hepatocellular carcinoma treatment within 3month or viable tumor Viable hepatocellular carcinoma Liver transplant Previous treatment with transjugular intrahepatic portosystemic stent shunt (TIPS) History of significant cardiac diseases such as recent myocardial infarction or ischemic diseases within 1 year of screening Prolonged QTc interval of > 500 ms based on electrocardiography 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) Pregnant or breast feeding Patients with galactose intolerance or malabsorption (as production of the drug contains lactose) HbA1Cc ≥ 9 % Serious medical illness (e.g. heart failure, severe pulmonary disorders, alcohol dependence, malignant tumors, etc)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Won Hyeok Choe, MD

Phone

82-2-2030-7506

20050101@kuh.ac.kr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

June Sung Lee, MD, PhD

Organizational Affiliation

Inje University Ilsan Paik Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Konkuk University Medical Center

City

Seoul

ZIP/Postal Code

143-729

Country

Korea, Republic of

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Won Hyeok Choe, MD

Phone

82-2-2030-5027

20050101@kuh.ac.kr

12. IPD Sharing Statement

Learn more about this trial

Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites

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