Tolvaptan to Reduce Length of Stay in Hospitalized Patients With Cirrhosis and Hyponatremia
| Status: | Terminated |
|---|---|
| Conditions: | Metabolic |
| Therapuetic Areas: | Pharmacology / Toxicology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 12/13/2017 |
| Start Date: | March 2012 |
| End Date: | March 2015 |
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.
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.
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.
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.
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
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