Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites (TONIC)

October 29, 2012 updated by: Won Hyeok Choe, Konkuk University Medical Center

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

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
105

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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
Time Frame: baseline and 28 days
baseline and 28 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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
Time Frame: baseline and 4 days
baseline and 4 days
the time to normalization of the serum sodium concentration
Time Frame: up to 28 days
up to 28 days
the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis
Time Frame: up to 28 days
up to 28 days
Abdominal discomfort based on a 100-mm visual analogue scales (VAS)
Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28
day 1, 2, 3, 4, 7, 14, 21, 28
The change in the dose of concomitant diuretics from baseline at day 28
Time Frame: day 1, 2, 3, 4, 7, 14, 21, 28
day 1, 2, 3, 4, 7, 14, 21, 28
the number of participants with serious adverse events
Time Frame: from baseline to day 28 after intervention
from baseline to day 28 after intervention
the time to ascites improvement
Time Frame: up to 28 days
up to 28 days
the time of worsening of ascites
Time Frame: up to 28 days
up to 28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Konkuk University Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
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

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: June Sung Lee, MD, PhD, Inje University Ilsan Paik Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2012

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2014

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 1, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 18, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 29, 2012

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 30, 2012

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 30, 2012

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 29, 2012

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • KUH1010412

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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