HyponatremiaPhase 4TONICNCT01716611
Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites
A Phase 4 study testing Tolvaptan in people with Hyponatremia and Ascites, run by Konkuk University Medical Center at 1 site in South Korea.
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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Hyponatremia, Ascites
- What is being tested?
- Tolvaptan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 105 participants
- Where
- 1 siteSouth Korea
- Study dates
- Nov 2012to Feb 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
South Korea1 site
Konkuk University Medical Center
Seoul, Seoul, 143-729
Won Hyeok Choe, MD, 82-2-2030-5027, 20050101@kuh.ac.kr
About this study
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
The purpose of the study is to investigate the efficacy and safety for the management of hyponatremia and ascites in patients with liver cirrhosis.
Read the 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
- Conditions
- Hyponatremia, Ascites
- Being tested
- Tolvaptan, placebo
- Keywords
- liver cirrhosis, hyponatemia, ascites, vaptans, antidiuretic hormon, arginine vasopressin
- Medical subject headings
- Hyponatremia, Ascites, Liver Cirrhosis, Diabetes Insipidus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolvaptanDrug
Also called SAMSCA
15 - 60 mg/day for 28 days
placeboDrug
| Study group | Role | What they receive |
|---|---|---|
| Tolvaptan group | Active comparator | Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days Receives: Drug: Tolvaptan |
| Placebo group | Placebo comparator | Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention
Measured: baseline and 28 days
Secondary outcomes (8)
the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4
Measured: baseline and 4 days
the time to normalization of the serum sodium concentration
Measured: up to 28 days
the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis
Measured: up to 28 days
Abdominal discomfort based on a 100-mm visual analogue scales (VAS)
Measured: day 1, 2, 3, 4, 7, 14, 21, 28
The change in the dose of concomitant diuretics from baseline at day 28
Measured: day 1, 2, 3, 4, 7, 14, 21, 28
the number of participants with serious adverse events
Measured: from baseline to day 28 after intervention
the time to ascites improvement
Measured: up to 28 days
the time of worsening of ascites
Measured: up to 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2012 (estimated)
- Study startNov 2012
- Primary completionJan 2014 (estimated)
- Study completionFeb 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HyponatremiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 105 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Konkuk University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Inje University, Korea University Anam Hospital, Hanyang University, Severance Hospital, Seoul St. Mary's Hospital, Samsung Medical Center, Chung-Ang University Hospital, Hallym University Medical Center, Inha University Hospital, Soonchunhyang University Hospital, Kyungpook National University Hospital, Incheon St.Mary's Hospital, Chungnam National University
- Responsible party
- Principal investigator, Won Hyeok Choe, Konkuk University Medical Center
- Investigators
- June Sung Lee, MD, PhD, Principal investigator, Inje University Ilsan Paik Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01716611
- Sponsor's protocol ID
- KUH1010412
- Acronym
- TONIC
- Status last verified
- Oct 2012
- First submitted
- 18 Oct 2012
- Last updated
- 30 Oct 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01716611
- Acronym / sponsor ID
- TONIC / KUH1010412
- Conditions
- Hyponatremia, Ascites
- Keywords
- liver cirrhosis, hyponatemia, ascites, vaptans, antidiuretic hormon, arginine vasopressin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 105 participants (estimated)
- Lead sponsor
- Konkuk University Medical CenterUniversity, hospital or other
- Collaborators
- Inje University, Korea University Anam Hospital, Hanyang University, Severance Hospital, Seoul St. Mary's Hospital, Samsung Medical Center, Chung-Ang University Hospital, Hallym University Medical Center, Inha University Hospital, Soonchunhyang University Hospital, Kyungpook National University Hospital, Incheon St.Mary's Hospital, Chungnam National University
- Study start
- Nov 2012
- Primary completion
- Jan 2014 (estimated)
- Study completion
- Feb 2014 (estimated)
- First posted
- 30 Oct 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tolvaptan group | Active comparator | Drug: TolvaptanForm : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days |
| Placebo group | Placebo comparator | Drug: placeboForm : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TolvaptanAlso: SAMSCA15 - 60 mg/day for 28 days | Drug | Tolvaptan group |
| placebo | Drug | Placebo group |
Primary outcome
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
8 secondary outcomes
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
the time to normalization of the serum sodium concentration
Time frame: 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
Abdominal discomfort based on a 100-mm visual analogue scales (VAS)
Time frame: 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
the number of participants with serious adverse events
Time frame: from baseline to day 28 after intervention
the time to ascites improvement
Time frame: up to 28 days
the time of worsening of ascites
Time frame: up to 28 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
June Sung Lee, MD, PhD principal investigator
Inje University Ilsan Paik Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tolvaptan in people with Hyponatremia and Ascites, run by Konkuk University Medical Center at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 30 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Won Hyeok Choe, MD (82-2-2030-7506, 20050101@kuh.ac.kr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2012.