Tolvaptan to Reduce Length of Stay in Hospitalized Patients With Cirrhosis and Hyponatremia
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Length of Hospital Stay
研究概览
简要总结
Hyponatremia is a condition in which there is a low sodium level in the blood. Individuals with cirrhosis may develop low blood sodium as a complication of their liver disease. In these patients, the presence of low blood sodium may exacerbate other complications such as encephalopathy, resulting in confusion, drowsiness, or coma. It may also affect the ability of the body to fight infection. In certain cases, cirrhotic patients may be hospitalized for the treatment of their low blood sodium.
The drug tolvaptan is currently FDA approved for the treatment of hyponatremia in patients with cirrhosis. Although it has been shown to increase the sodium level, the clinical trials that led to its approval did not otherwise assess clinical benefit of the drug.
This study is designed to determine whether patients with cirrhosis derive a clinical benefit when they receive tolvaptan for the treatment of hyponatremia within 2 days of admission. Specifically, whether it is associated with shortened length of stay and improvement in other complications of cirrhosis.
详细描述
As per hyponatremia standard treatment of care, all patients considered for the study will have had diuretic therapy discontinued for at least 1 day prior to the screening visit and received volume expansion with 25% salt poor albumin, if clinically indicated to ensure adequate intravascular volume expansion as standard of care for a patient hospitalized for complications of cirrhosis.
Patients will be approached and presented with a written consent form during the first 24 hours of their admission to NYUMC (Tisch Hospital). They will be verbally informed about the purpose and procedures of the study, as well as its potential risks and benefits. Following written consent, the patients will undergo a series of screening procedures, including physical examination, medical history, blood work, and hepatic encephalopathy assessment, to determine their eligibility.
After screening and determination that the patient fulfills all inclusion and exclusion criteria, the patients will be randomized the following day on Day 0 to receive oral tolvaptan or placebo once daily. Patients in the treatment arm will receive oral tolvaptan at an initial dose of 15mg once daily. The placebo arm will be used as a comparison group to determine whether long-term, ambulatory tolvaptan administration is associated with clinical benefits to patients with cirrhosis and hyponatremia. Patients in the placebo arm will receive current standard of treatment for patients with cirrhosis and hyponatremia. Current standard treatment of hyponatremia in cirrhotic patients involves fluid restriction in the diet (1L fluid daily), discontinuation of diuretic therapy (such as furosemide, spironolactone), and frequent monitoring of the sodium level. Severe hyponatremia (Na<120mEq/L) involves infusion of hypertonic saline.
Patients will be encouraged to drink in response to thirst, and patients will be re-evaluated at 8 hours with determination of Na level after the first dose. If the serum sodium concentration remains below 136 mEq/L or increases by less than 5 mEq/L during the prior 24 hours, the dose will be increased from 15mg to a maximum dose of 30mg. Too rapid correction of serum sodium will be defined as either 8 mEq/L in the first 8 hours or greater than 12mEq/L over 24 hours. In these situations, tolvaptan will either be withheld or decreased at the next dose or the patient instructed to increase fluid intake. Similar adjustments will be made if the serum sodium concentration rises above 145mEq/L.
Patients will undergo a physical examination and laboratory evaluation that will include electrolytes, BUN/Cr, and liver tests and determination for reason for continued hospitalization as per standard of care from Day 1 to 8 or until day of discharge if discharge occurs prior to Day 8. Neutrophil function assay will be obtained upon randomization and at week 4 after discharge. Urine electrolytes and renin and copeptin levels will be obtained at Day 0, Day 8 (if still hospitalized), day of discharge, and monthly.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cirrhosis
- •Screening within 24 hours of admission
- •Na level less than 130mEq/L
- •Presence of fluid overload with either history of ascites or edema
- •Cr < 2.0mg/dl
- •Planned length of stay after randomization of at least 24 hours
- •Anticipated survival of at least 8 days
- •Ability to provide informed consent
排除标准
- •Hospitalization greater than 24 hours at screening
- •Depletional hyponatremia
- •Hyponatremia due to hyperglycemia
- •Acute and transient hyponatremia associated with head trauma or post-operative states
- •Hyponatremia due to primary polydipsia, adrenal insufficiency, or hypothyroidism
- •Urgent need for treatment of hyponatremia with saline or hypertonic saline
- •Treatment with demeclocycline, lithium chloride, and urea
- •Cr greater than 2.0mg/dl
- •Stage 3 or 4 hepatic encephalopathy
- •Inability to provide informed consent
- •Planned discharge within 24 hours
- •Anticipated survival less than 8 days
- •GI bleeding within one month of enrollment
研究组 & 干预措施
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Placebo (Drug)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Hepatic Encephalopathy Assessment (Behavioral)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Quality of Life Assessment (Behavioral)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Vital signs (Biological)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Blood laboratory tests (Biological)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Ascites Evaluation (Procedure)
Placebo
Subjects will receive placebo once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Edema (Procedure)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Tolvaptan (Drug)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Hepatic Encephalopathy Assessment (Behavioral)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Quality of Life Assessment (Behavioral)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Vital signs (Biological)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Blood laboratory tests (Biological)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Ascites Evaluation (Procedure)
Tolvaptan
Subjects will receive Tolvaptan once daily.
They will undergo the following procedures in every visit: Vitals (blood pressure, heart rate, respiration, temperature, weight, height), Laboratory Tests (chemistry, hematology, liver function, urine electrolytes, renin, and copeptin), ascites assessment, evaluation for edema. Quality of life assessments (SF-36, and LDQOL 1.0) will be administered on Day 1, Discharge day, Weeks 1-4 post-discharge, and months 2-6 post-discharge. Hepatic encephalopathy assessment (Number Connection Test, Digit symbol test, Constructional apraxia, Inhibitory control test, Repeatable Battery for the Assessment of Neuropsychological Status) will be administered on Days 1, 2, 4, 6, and 8; discharge day; Weeks 1-4 post-discharge; and Months 2-6 post-discharge.
干预措施: Edema (Procedure)
结局指标
主要结局
Length of Hospital Stay
时间窗: participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Performance period for sponsored trial expired and not enough subjects were enrolled in study. Funding sponsor did not continue support.
次要结局
- Severity of Hepatic Encephalopathy(Months 2-6 post-discharge)
- Ascites(Day 1 to Post-discharge (6 months))
- Renal Function [BUN and Creatinine Laboratory Results](Day 1 to Post-discharge (6 months))
- Hospital Readmission Rate(Post-Discharge (6 months))
- Survival(Post-discharge (6 months))
- Neutrophil Function [Results From the Assay of Neutrophils](Day 1 to Post-discharge (6 months))
- Tolerability of Diuretic Therapy(Day 1 until Discharge (participants will be followed for the duration of hospital stay, an expected average of 2 weeks))