Effect of Probiotics in Non-alcoholic Fatty Liver Disease and Steatohepatitis

Study Overview
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Brief Summary
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This study will evaluate the effect of probiotics, a beneficial intestinal bacteria supplement, if it will cause improvement of the non-alcoholic fatty liver disease (NAFLD) and or non-alcoholic steatohepatitis (NASH- an inflammation with concurrent fatty accumulation of the liver) as measured by transient elastography - an ultrasound of the liver that assess the elastic properties (density) and stiffness of the liver tissue. This study will enroll patients 18 years and older with diagnosis of NAFLD and or NASH.

Detailed Description
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Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are conditions without symptoms where inflammation in the liver can progress to end-stage liver disease (cirrhosis). Current standard of care for these conditions include control of metabolic syndrome which includes but is not limited to a patient's high blood pressure (hypertension), high cholesterol (hyperlipidemia), high blood sugar (hyperglycemia) and excess fat around the waist (central obesity and waist circumference) with lifestyle modifications including diet, exercise and medications. While the mechanism for inflammation on the liver in NAFLD and NASH is not completely understood, the American Association for the Study of Liver Diseases currently suspects it may be connected with the metabolism in the bowel and subsequent hepatic (liver) circulation. The bacteria of the intestines (microbiome or gut flora) may play a role in the inflammatory cascade through the bloodstream that affects the liver. The World Health Organization (WHO) and the Food and Agricultural Organization (FAO) of the United Nations define Probiotics as a live microorganism which, when taken in adequate amounts confer a health benefit in the gastrointestinal tract. This study will be done to determine if probiotic use may be a viable treatment option for NAFLD and NASH and to establish a link that the intestinal microbiome or gut flora plays a role in liver inflammation which will be measured by elastography. Patients with NAFLD and NASH seen in office consultation of the investigator will be approached to participate in the randomized like a flip of a coin, double-blind (patients and researchers will be blinded), placebo controlled study. Participant will be counseled on diet and exercise. The participants will receive information on a standardized Mediterranean diet based nutrition program as well as direction for recommended 30 minutes of aerobic exercise 3 times weekly. A baseline transient elastography, blood test such as liver enzymes Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) will be drawn, including hemoglobin A1C (diabetic marker), cholesterol in the form of Low-Density Lipoprotein (LDL/bad cholesterol) and assessment of Body Mass Index (BMI). Participants will be randomized by pharmacy into 2 groups, a control group and a treatment group. The treatment group will be provided with a 6 month supply of Align probiotic once daily supplementation; the control group will be given a placebo for 6 months along with both groups given instructions on how to take the supplement. Subjects will receive a 1 month phone call follow up to ensure adherence to study instructions and daily oral intake of supplement, and again at 3 months. Study participation will end at 6 months after the repeat of liver enzymes, hemoglobin A1C, lipid panel, assessment of BMI and transient elastography as completed at scheduled clinical appointment.

Official Title
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Effect of Probiotics in Non-Alcoholic Fatty Liver Disease and Steatohepatitis Measured by Transient Elastography (PRONE Study).

Conditions
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Fatty Liver Disease, Fibrosis, Liver, Cirrhosis, Liver, Steatohepatitis, Nonalcoholic

Intervention / Treatment
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* Drug: Align Probiotic Supplement Capsule
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of NAFLD and/or NASH Subject aged 18 and older Non-pregnant - Self-reported Subject with decision making capacity to understand and consent to study procedures Ability to follow study related activities regarding medications, diet and exercise Exclusion Criteria: Without diagnosis of NAFLD or NASH History of liver disease from other causes, including but not limited to hepatitis, autoimmune, alcohol use, fatty liver of pregnancy, Wilson's disease, primary or secondary hemochromatosis Patients aged less than 18 years Self-reported pregnant patients Inability to understand, follow and consent to study procedures Hepatic decompensation defined as gastrointestinal bleeding, ascites, hepatic encephalopathy Inability to engage in exercise Currently immunocompromised or taking immunosuppressive drugs Milk protein allergy Recent or active chemotherapy for malignancy Gastrointestinal malignancy Gastrointestinal disease such as Ulcerative Colitis, Crohn's Disease as these alter the microbiome Recent antibiotic therapy (within 6 months) Known allergy to probiotics History of major gastrointestinal surgery such as resection of the colon No concomitant use of probiotic from any source (i.e., kefir, certain yogurts, live culture, sauerkraut) Liver scan >2 months prior to enrollment Weight loss >5 pounds in the last 2 months Any implanted battery operated device (i.e. AICD, pacemaker, loop recorder, cochlear implant)

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
Interventional Model Description: Prospective, randomized, double-blind study. Participant will be randomized to either the Treatment (Probiotic) Group or the Control (Placebo) Group.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Group: Probiotic<br>Probiotic 1 billion units Supplement Once Daily | Drug: Align Probiotic Supplement Capsule<br>* Align Probiotic 1 billion units, 1 capsule once daily<br>* Other names: Probiotic;|
| Placebo Comparator: Control Group: Placebo<br>Placebo Capsule Once Daily | Drug: Placebos<br>* Placebos capsule 1 capsule Once daily<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probiotic Effects on Liver Fibrosis | Probiotic effects on liver fibrosis as measured by transient elastography, as a change from baseline to 6 months, measured on a scale from 1-4. 1= a clinical grade of F0-F1 and represents 2-7 kilopascals in elastography testing. 4= a clinical grade of F4 and represents 14 kilopascals or higher in elastography testing. A higher score on the scale represents worsening liver scarring. Positive numbers indicate an increase in fibrosis; negative numbers indicate decrease in fibrosis. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probiotic Effects on Liver Enzymes, AST | Probiotic effects on Liver enzymes, AST as a change from baseline to 6 months, measured in units per liter. Positive numbers indicate an increase in AST; negative numbers indicate decrease in AST | 6 months | 
| Probiotic Effects on Liver Enzymes, ALT | Probiotic effects on Liver enzymes, ALT as a change from baseline to 6 months, measured in units per liter. Positive numbers indicate an increase in ALT; negative numbers indicate decrease in ALT | 6 months | 
| Probiotic Effects on Diabetic Markers | Probiotic effects on Diabetic Markers as measured by hemoglobin A1C blood test as a change from baseline to 6 months, measured in percent. Positive numbers indicate an increase in hemoglobin A1c; negative numbers indicate decrease in hemoglobin A1c | 6 months | 
| Probiotic Effects on BMI | Probiotic effects on Body Mass Index (BMI) wherein weight and height will be combined to report BMI in kg/m^2 as a change from baseline to 6 months. Positive numbers indicate an increase in BMI; negative numbers indicate decrease in BMI. | 6 months | 
| Probiotic Effects on LDL | Probiotic effects on Low-density Lipoprotein (LDL) as a change from baseline to 6 months, measured in milligrams per deciliter. Positive numbers indicate an increase in LDL; negative numbers indicate decrease in LDL | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fatty Liver, Fibrosis, Cirrhosis, Probiotic, Steatohepatitis, Elastography