A Randomized Comparison of Rifaximin Versus Lactulose in Hospitalized Cirrhotic Patients With Renal Failure

Study Overview
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Brief Summary
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The aim of the current study is to determine whether rifaximin or lactulose is more effective in preventing the development of severe hepatic encephalopathy in hospitalized patients with cirrhosis and new onset kidney failure. Subjects will be randomly assigned to one of two treatment groups: Group A: Lactulose 20g dose titrated to 2-3 soft-formed bowel movements per day Group B: Rifaximin 550mg tablet twice daily. Subjects will be followed daily for two weeks or until hospital discharge. Treatment success is defined as prevention of grade 3 or 4 HE during hospitalization.

Detailed Description
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Hepatic Encephalopathy (HE) is a reversible neuropsychiatric syndrome that develops in patients with cirrhosis due to the accumulation of a variety of toxic substances that are produced from bacteria in the gastrointestinal tract. It is characterized by slowing of function of the brain function and ranges in severity from mild cognitive impairment (grade 1), presence of a shaking tremor called asterixis (grade 2), lethargy but arousable state (grade 3), and coma (grade 4). Decreased kidney function exacerbates the condition, and hospitalized patients with cirrhosis with new onset kidney failure are at risk for the development of severe HE. Possible treatments for HE include lactulose and antibiotics. Lactulose reduces the production of many of the toxins by the bacteria, and antibiotics work by reducing the number of bacteria in the gastrointestinal tract. Rifaximin is an antibiotic that is an antibiotic that is not absorbed, possesses a wide antibacterial spectrum, and was approved by the Food and Drug Administration in 3/2010 for prevention of relapse for patients with recurrent severe hepatic encephalopathy. The aim of the current study is to determine whether rifaximin or lactulose is more effective in preventing the development of severe hepatic encephalopathy in hospitalized patients with cirrhosis and new onset kidney failure. To determine whether rifaximin or lactulose is more effective in preventing severe HE, seventy consecutive hospitalized patients with cirrhosis and new onset kidney failure will be recruited. New onset kidney failure will defined as a progressive and sustained increase in serum creatinine >0.5mg/dl from baseline to a value of 2.0mg/dl or greater within 3 days. Subjects will be randomly assigned to one of two treatment groups: Group A: Lactulose 20g dose titrated to 2-3 soft-formed bowel movements per day Group B: Rifaximin 550mg tablet twice daily. Subjects will be followed daily for two weeks or until hospital discharge. Severity of hepatic encephalopathy will be graded by physical examination, review of hospital chart, and performance of standard paper and pencil tests that evaluates the ability to concentrate. In addition, approximately one tablespoon will be drawn twice a week at every 3 to 4 day for ammonia level and other toxins. A sample of breath will also be collected by having the subjects breathe into a collection bag to measure substances that determine whether there are bacteria present in the small intestine. Treatment success is defined as prevention of grade 3 or 4 HE during hospitalization.

Official Title
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A Randomized Comparison of Rifaximin Versus Lactulose in Hospitalized Cirrhotic Patients With Renal Failure

Conditions
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Hepatic Encephalopathy

Intervention / Treatment
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* Drug: Rifaximin
* Drug: Lactulose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Cirrhosis of the liver based on biopsy or clinical and radiographic criteria Ability to provide informed consent (Grade 0 to 1 HE) Acute renal failure (increase in baseline creatinine of 0.5mg/dL to a value of >2.0 mg/dL within 3 days). Absence of improvement in renal function after adequate fluid resuscitation using either normal saline or blood products (25% salt poor albumin, fresh frozen plasma, or packed red blood cells) Exclusion Criteria: Previous history of sensitivity/allergy to lactulose or rifaximin or rifampin Pregnancy Inability to obtain informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin<br> | Drug: Rifaximin<br>* (Xifaxin®, Salix Pharmaceuticals) 550mg tablet twice daily.<br>* Other names: Xifaxin;|
| Experimental: Lactulose<br> | Drug: Lactulose<br>* 20g dose titrated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of Progressive Hepatic Encephalopathy to Stage 3 or 4 in patients with progressive renal failure | The primary outcome for this study is the development of progressive hepatic encephalopathy to stage 3 or 4 in patients with progressive renal failure. For the purpose of this study, acute renal failure is defined as a progressive and sustained increase in serum creatinine >0.5mg/dl from baseline to a value of 2.0mg/dl, irrespective of etiology in 3 days. Renal failure is progressive and sustained if there is no improvement after volume resuscitation with 1.5 L of normal saline or equivalent colloid infusion (serum albumin or blood product transfusion). | 90 days (including follow-ups) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality |  | Patient's hospital stay up to 14 days | 
| Hospital Length of Stay |  | Up to 14 days |