Probiotic Lactobacillus GG (LGG) in Patients With Minimal Hepatic Encephalopathy

Study Overview
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Brief Summary
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This research proposes to find whether the probiotic lactobacillus GG is safe and well tolerated in patients with minimal hepatic encephalopathy. We also want to get insight into the mechanisms of action of LGG.

Detailed Description
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Development of complementary and alternative medicine approaches to liver disease is a priority area at NCCAM. Minimal hepatic encephalopathy (MHE) is a significant complication of cirrhosis which can result in poor quality of life, impaired cognition and difficulty in driving motor vehicles with a high traffic accident risk. MHE is estimated to affect one half of the 5.5 million cirrhotics in the U.S. Despite these negative outcomes, there is no consensus on treatment of MHE. Currently available therapies for MHE act on intestinal flora but are limited by adverse effects (i.e. lactulose-induced diarrhea), which negatively impact adherence. Probiotic bacterial supplements, which also act on intestinal flora, are an emerging therapy for MHE. Our group has performed a pilot, randomized trial which demonstrated a significantly higher rate of MHE reversal with excellent adherence in patients randomized to probiotic yogurt compared to no therapy. This proposal intends to define Lactobacillus GG (LGG) as a biologically-based alternative therapy for MHE with special focus on metabolic and stool bacteriologic changes. The hypothesis of this Phase I proposal is: LGG will be safe and efficacious for the treatment of minimal hepatic encephalopathy compared to placebo in a randomized, double-blind trial. This will be carried out with four specific aims: Specific aim 1: To define the safety and tolerability of LGG in patients with minimal hepatic encephalopathy against placebo in a Phase I randomized controlled trial. Specific aim 2: To define the effect of LGG on intestinal microflora composition in cirrhotics with minimal hepatic encephalopathy using 16s stool DNA sequencing in a randomized, placebo-controlled trial. Specific aim 3: To determine the effect of LGG on metabolic biomarkers and cytokines in stool, urine and blood using nuclear magnetic resonance spectroscopy in minimal hepatic encephalopathy. Specific aim 4: To determine the effect of LGG on psychometric function in patients with minimal hepatic encephalopathy. The specific aim and sub-aims will be tested in 30 patients with non-alcoholic cirrhosis and MHE: 15 randomized to LGG and 15 randomized to placebo to be taken BID for 8 weeks with detailed psychometric, metabolic, anthropometric and bacteriologic evaluation. Results generated from this study will form the basis for a RO1 proposal to develop the use of probiotics as a biologically-based alternative treatment with long-term outcomes of prognosis, development of overt encephalopathy and prevention of traffic accidents in patients with MHE.

Official Title
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Probiotic LGG in Patients With Minimal Hepatic Encephalopathy

Conditions
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Minimal Hepatic Encephalopathy

Intervention / Treatment
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* Biological: Lactobacillus GG
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-65 years Histological evidence of cirrhosis Maintenance of cirrhosis treatment and stability for 6 months Mini-mental state exam score > 25 Presence of MHE on psychometric testing Exclusion Criteria: Rx for MHE or OHE Antibiotics within 6 weeks Yogurt consumption within 2 weeks Neutrophil count < 500 Inflammatory bowel disease History of pancreatitis Hepato-cellular carcinoma Recent (6 weeks) gastrointestinal bleed Recent (6 months) alcohol intake Psychoactive medications (including interferon/antipsychotics) Liver transplant

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lactobacillus GG<br> | Biological: Lactobacillus GG<br>* 1 capsule of lactobacillus GG BID compared to placebo BID<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* 1 capsule of lactobacillus GG BID compared to placebo BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of LGG |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life measured by sickness impact profile |  | 3 years | 
| Bacteriology measured in the stool flora by specialized non-culture techniques |  | 3 years | 
| Metabonomics and psychometric testing using a standard psychometric battery |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, hepatic encephalopathy, complications, probiotic, lactobacillus GG