Efficacy and Safety of E.Coli Nissle 1917 in Patients With Mild (Stage 1-2) or Minimal Hepatic Encephalopathy

Study Overview
=================
Brief Summary
-----------------
The purpose of study to assess the short-term efficacy and safety of probiotic E.coli Nissle 1917 strain comparing to lactulose and rifaximin in patients with mild (Stage 1-2) or minimal hepatic encephalopathy

Official Title
-----------------
Probiotic E.Coli Nissle 1917 Comparing to Lactulose and Rifaximin in Patients With Mild (Stage 1-2) or Minimal Hepatic Encephalopathy

Conditions
-----------------
Hepatic Encephalopathy, Liver Cirrhosis, End Stage Liver DIsease

Intervention / Treatment
-----------------
* Dietary Supplement: E.coli Nissle 1917
* Drug: Lactulose
* Drug: Rifaximin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Cirrhosis diagnosed on the basis of liver biopsy, liver stiffness measurement or radiological study; presence of minimal or mild (Grade 1-2) HE as defined by West Haven criteria; two or more documented episodes of HE in the last 6 months, in addition to at least one episode in the last 3 months; subject is capable and willing to comply with all study procedures; signed inform consent. Exclusion Criteria: history of taking L-ornithine- L -aspartate, zinc, metronidazole, or neomycin, antibiotics, probiotics and yogurt consumption within 6 weeks; subject has a history of allergy or intolerance to lactulose and/or rifaximin; alcohol intake during the past 6 month or during follow up; recent (6 weeks) gastro-intestinal bleed; hepato-cellular carcinoma or liver transplantation; renal insufficiency; significant comorbid illness such as heart or respiratory failure; concurrent infection such as spontaneous bacterial peritonitis, pneumonia or urinary tract infection; any neurologic diseases such as alzheimer's disease, parkinson's disease and nonhepatic metabolic encephalopathies; subject has any condition or circumstance that would, in the opinion of the Investigator, prevent completion of the study or interfere with analysis of study results, including history of noncompliance with treatments.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E.coli Nissle 1917<br>probiotic, oral, for the first 4 days, 1 capsule, and then 2 capsules per day for 1 month treatment | Dietary Supplement: E.coli Nissle 1917<br>* Probiotic contains biomass of E.coli Nissle 1917, 2,5-25·109 colony forming units - CFU/g<br>* Other names: MUTAFLOR capsules;|
| Active Comparator: Lactulose<br>will receive 30-60 ml of lactulose in 2 or 3 divided doses so that patient passed 2-3 semisoft stools per day, 1 months of treatment | Drug: Lactulose<br>* will receive 30-60 ml of lactulose in 2 or 3 divided doses so that patient passed 2-3 semisoft stools per day, 1 months of treatment<br>* Other names: DUPHALAC;|
| Active Comparator: Rifaximin<br>rifaximin, oral, 500 mg BID, 1 months of treatment | Drug: Rifaximin<br>* rifaximin, oral, 500 mg BID, 1 months of treatment<br>* Other names: Alfa Normix;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Stroop test |  | 1 month | 
| Change in serum ammonia |  | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum inflammatory cytokine | The level of IL-6, IL-8 and INFγ in pg / ml will be assesed | 1 month | 
| Bacteriology measured in the stool flora by specialized non-culture techniques | The percentage of patients in each group were evaluated and characterized by a decrease below the normal content of symbiotic bacteria Bifidobacterium (less than 107 CFU / g), lactobacilli (less than 107 CFU / d), E.coli with normal properties (less than 106 CFU / d) and increase in content E.coli with altered properties (more than 106 CFU / g), pathogenic enterobacteria (not normally detected) and fungi of the genus Candida (more than 104 CFU / d) | 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hepatic encephalopathy, Liver Cirrhosis, End Stage Liver DIsease, E.coli Nissle 1917, Probiotic, lactulose, rifaximin