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
试验速览
- 阶段
- 4 期
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention
研究概览
简要总结
The purpose of the study is to investigate the efficacy and safety for the management of hyponatremia and ascites in patients with liver cirrhosis.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Tolvaptan group
Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
干预措施: Tolvaptan (Drug)
Placebo group
Form : Tablet, Dosage: 15 mg, 30 mg or 60 mg, Frequency: once a day. Duration: 28days
干预措施: placebo (Drug)
结局指标
主要结局
the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 28 after intervention
时间窗: baseline and 28 days
次要结局
- 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)
- the time to normalization of the serum sodium concentration(up to 28 days)
- the time to first paracentesis, number of paracentesis, the volume of ascitic fluid obtained from paracentesis(up to 28 days)
- Abdominal discomfort based on a 100-mm visual analogue scales (VAS)(day 1, 2, 3, 4, 7, 14, 21, 28)
- The change in the dose of concomitant diuretics from baseline at day 28(day 1, 2, 3, 4, 7, 14, 21, 28)
- the number of participants with serious adverse events(from baseline to day 28 after intervention)
- the time to ascites improvement(up to 28 days)
- the time of worsening of ascites(up to 28 days)
研究者
Won Hyeok Choe
Associate Professor
Konkuk University Medical Center