Clinical trial NCT01890694: Tolvaptan to Reduce Length of Stay in Hospitalized Patients With Cirrhosis and Hyponatremia
Official title: Tolvaptan to Reduce Length of Stay in Hospitalized Patients With Cirrhosis and Hyponatremia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Hyponatremia
Keywords: Hyponatremia
Dilutional Hyponatremia
Euvolemic Hyponatremia
Hypervolemic Hyponatremia
Fluid Restriction
Tolvaptan
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: Otsuka America Pharmaceutical
First posted: 2013-07-02
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Patients will undergo a detailed assessment for hepatic encephalopathy on Days 0, 2, 4, and 8 or until day of discharge if it occurs prior to Day 8. Patients will also have a complete assessment on day of discharge if occurs after Day 8. Quality of life questionnaires will be completed at Day 0, Day 8 (optional), day of discharge (optional), and weekly for the first month and then monthly for a total of 3 months after discharge. In addition, patients will be asked to complete the questionnaires during their follow-up visits, which will occur 1, 2, and 4 weeks after study drug discontinuation.

Patients with clinically significant fluid overload (moderate ascites, grade 1 edema), Na level 130 or greater, asterixis is not present, and severe azotemia is not present (BUN less than 30mg/dl, Cr less than 1.5mg/dl) will be started on spironolactone 50mg daily and furosemide 20mg daily. Doses will be increased by 50mg and 20mg, respectively, daily every week if clinically significant fluid overload persists, weight loss over the previous week was less than 5 lbs, and the above safety assessments remain satisfied. Diuretic doses will be either reduced or held for excessive fluid loss (more than 10 lbs over the previous week) or one of the safety parameters are present.

At discharge, patients will continue on Study Drug with weekly visits for one month and then monthly, after discharge, for 3 months. At each visit, patients will have an interim history (need for hospitalization), performance of large volume paracentesis and volume of ascites removed, physical examination, liver and kidney tests, and assessment of hepatic encephalopathy.

Following the discontinuation of the study drug, patients will be asked to come to the clinic for follow-up visits at weeks 1, 2, and 4, post-discontinuation of study drug. At each visit, patients will have an interim history (need for hospitalization), performance of large volume paracentesis and volume of ascites removed, physical examination, liver and kidney tests, and assessment of hepatic encephalopathy.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Length of Hospital Stay
timeFrame: participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Secondary outcomes:
measure: Severity of Hepatic Encephalopathy
timeFrame: Day 2
measure: Severity of Hepatic Encephalopathy
timeFrame: Day 4
measure: Severity of Hepatic Encephalopathy
timeFrame: Day 6
measure: Severity of Hepatic Encephalopathy
timeFrame: Day 8
measure: Severity of Hepatic Encephalopathy
timeFrame: participants will be followed for the duration of hospital stay, an expected average of 2 weeks
measure: Severity of Hepatic Encephalopathy
timeFrame: Week 1-4 Post-discharge
measure: Severity of Hepatic Encephalopathy
timeFrame: Months 2-6 post-discharge
measure: Ascites
timeFrame: Day 1 to Post-discharge (6 months)
measure: Renal Function [BUN and Creatinine Laboratory Results]
timeFrame: Day 1 to Post-discharge (6 months)
measure: Hospital Readmission Rate
timeFrame: Post-Discharge (6 months)
measure: Survival
timeFrame: Post-discharge (6 months)
measure: Neutrophil Function [Results From the Assay of Neutrophils]
timeFrame: Day 1 to Post-discharge (6 months)
measure: Tolerability of Diuretic Therapy
timeFrame: Day 1 until Discharge (participants will be followed for the duration of hospital stay, an expected average of 2 weeks)
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
Study officials:
affiliation: NYU School of Medicine
name: Samuel Sigal, MD
role: PRINCIPAL_INVESTIGATOR
References: