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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
Sponsored by
Konkuk University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

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:

  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)

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

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

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
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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
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

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
No
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
Email
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
Email
20050101@kuh.ac.kr

12. IPD Sharing Statement

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Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites

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