Efficacy and Safety of a Probiotic Composition as Adjunct in MAFL Management

Study Overview
=================
Brief Summary
-----------------
Some studies have shown beneficial results with probiotics on hepatic function of subjects with fatty liver, but significant variability has been noted among probiotic formulations. This study aims at providing a comprehensive characterization of the effect of a particular probiotic formula in hepatic function of said subjects.

Detailed Description
-----------------
Some studies have shown beneficial results with probiotics on hepatic function of subjects with Non-Alcoholic Fatty Liver (NAFL) also known as Metabolism-Associated Fatty Liver (MAFL). However, meta-analyses have found significant variability among probiotic formulations. In fact, many probiotic properties are thought to be strain-specific. This study aims at providing a comprehensive characterization of a particular probiotic formula containing Lactoplantibacillus plantarum (formerly Lactobacillus plantarum) and Levilactobacillus brevis (formerly Lactobacillus brevis) in hepatic function of individuals with NAFL. The study will assess hepatic stiffness via transient elastography (Fibroscan), hepatic function via liver enzymes in serum (ALT, AST, GGT) and liver-specific inflammation via cytokeratin18 in serum, as well as some general metabolic and inflammatory markers.

Official Title
-----------------
Efficacy and Safety of a Probiotic Composition as Adjunct Treatment in the Comprehensive Management of Metabolism-Associated Hepatic Steatosis in Adults

Conditions
-----------------
Non Alcoholic Fatty Liver

Intervention / Treatment
-----------------
* Dietary Supplement: Probiotic composition
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Hepatic Steatosis associated with Metabolism (MAFL, also known as Non-Alcoholic Fatty Liver or NAFL) with Controlled Attenuation Parameter (CAP) value of > 269 dB / m when evaluated by Fibroscan transient elastography Alanine aminotransferase (ALT) levels at least 35% above the upper limit of reference values BMI between 25 and 40 kg / m2 Signing of the informed consent and understanding of the procedures to be carried out Not willing to change their current dietary habits (hypercaloric and hyperlipemic) Exclusion Criteria: Treatment of NAFL or NASH (Non-Alcoholic Steato-Hepatitis) for at least 3 months prior to the study, with high dose vitamin E (≥200 mg / day), high dose omega-3 (≥500 mg / day), pioglitazone, bile acid sequestrants, statins, GLP-1 agonists, and / or DPP4 inhibitors (gliptins), and not having shown a significant biochemical and ultrasonographic improvement History of chronic alcohol or drug abuse Diagnosis of infectious hepatitis or HIV infection Diagnosis of hemochromatosis Celiac disease, inflammatory bowel disease, chronic or recurrent diarrhea Chronic use of laxatives. Pancreatic failure, thyroid dysfunction, severe liver disease, biliary dysfunction (including cholecystectomy and blood bilirubin abnormalities) Uncontrolled diabetes or hypertriglyceridemia greater than 500mg / dL History of regular use (> 3 days) of oral or parenteral antibiotics one month prior to the study Current use of systemic corticosteroids, androgens, clopidogrel, digoxin, acenocoumarol, warfarin, phenytoin, topiramate, lithium, tricyclic antidepressants, monoamine oxidase inhibitors, second generation antipsychotics, amiodarone, tamoxifen, and/or diltiazem. Intake of other probiotics, plant-derived sterols, beta-glucans, red rice yeast (Monascus purpureus), or milk thistle extract (Silybum marianum) or its active ingredients (silymarin, silybin) on a regular basis (> 7 days) in the 15 days prior to entering the study. History of angina or cardiovascular events, cancer, or immunosuppression Chronic, moderate-to-heavy smoking (> 5 cigarettes a day) History of gastro-intestinal surgery in the previous year. Debilitating diseases (advanced liver or kidney disease, severe depression, psychotic symptoms, neurological diseases). Current pregnancy (positive urine test), or planning to become pregnant during the course of the study. Breastfeeding at the time of eligibility assessment Subjects having participated in a clinical study within 1 month prior to eligibility assessment Current use of 4 or more concomitant medications of any type

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 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
Interventional Model Description: Randomized, double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Probiotic composition<br>A capsule containing a mix of probiotic strains (1.5 x 10^9 CFU/capsule ) administered once daily for 4 months | Dietary Supplement: Probiotic composition<br>* Mixture of two Lactoplantibacillus plantarum strains (formerly Lactobacillus plantarum) and one Levilactobacillus brevis strain (formerly Lactobacillus brevis), in a maltodextrin carrier (E1400)<br>|
| Placebo Comparator: Placebo<br>A capsule containing placebo administered once daily for 4 months | Other: Placebo<br>* Maltodextrin (E1400, qs)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in alanine amino transferase (ALT) | Change in serum levels (international units/L) of alanine amino transferase (ALT) across the study. Sample obtained through blood sampling | change month 2 from baseline | 
| Change in alanine amino transferase (ALT) | Change in serum levels (international units/L) of alanine amino transferase (ALT) across the study. Sample obtained through blood sampling | change month 4 from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic steatosis | Change in the severity of the degree of hepatic steatosis measured by transient elastography with controlled attenuation parameter (Fibroscan CAP®) | change month 2 from baseline | 
| Change in hepatic steatosis | Change in the severity of the degree of hepatic steatosis measured by transient elastography with controlled attenuation parameter (Fibroscan CAP®) | change month 4 from baseline | 
| Change in Fibroscan-AST score | Change in the values of the Fibroscan-AST score (FAST, ranging 0-1), where higher values indicate a worse condition | change month 2 from baseline | 
| Change in Fibroscan-AST score | Change in the values of the Fibroscan-AST score (FAST, ranging 0-1), where higher values indicate a worse condition | change month 4 from baseline | 
| Change in Fatty Liver Index | Change in the values of the Fatty Liver Index (FLI, ranging 0-100), where higher values indicate a worse condition | change month 2 from baseline | 
| Change in Fatty Liver Index | Change in the values of the Fatty Liver Index (FLI, ranging 0-100), where higher values indicate a worse condition | change month 4 from baseline | 
| Change in Hepatic Steatosis Index | Change in the values of the Hepatic Steatosis Index (HSI, ranging 0-100), where higher values indicate a worse condition | change month 2 from baseline | 
| Change in Hepatic Steatosis Index | Change in the values of the Hepatic Steatosis Index (HSI, ranging 0-100), where higher values indicate a worse condition | change month 4 from baseline | 
| Change in Cholesterol | Change in LDL cholesterol, oxidized LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, total cholesterol. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in Cholesterol | Change in LDL cholesterol, oxidized LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, total cholesterol. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in leptin serum parameters | Change in leptin. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in leptin serum parameters | Change in leptin. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in adiponectin serum parameters | Change in adiponectin. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in adiponectin serum parameters | Change in adiponectin. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in HOMA serum parameters | Change in HOMA (Homeostatic Model Assessment). Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in HOMA serum parameters | Change in HOMA (Homeostatic Model Assessment). Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in glucose serum parameters | Change in glucose. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in glucose serum parameters | Change in glucose. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in glycosylated hemoglobin serum parameters | Change in glycosylated hemoglobin (Hb1Ac). Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in glycosylated hemoglobin serum parameters | Change in glycosylated hemoglobin (Hb1Ac). Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in insulin serum parameters | Change in insulin. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in insulin serum parameters | Change in insulin. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in Triglycerides serum parameters | Change in Triglycerides. Sample obtained through blood sampling. | change month 2 from baseline | 
| Change in Triglycerides serum parameters | Change in Triglycerides. Sample obtained through blood sampling. | change month 4 from baseline | 
| Change in ferritin serum parameters | Change in ferritin. Samples obtained through blood sampling | change month 2 from baseline | 
| Change in ferritin serum parameters | Change in ferritin. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in C-reactive protein serum parameters | Change in ferritin. Samples obtained through blood sampling | change month 2 from baseline | 
| Change in C-reactive protein serum parameters | Change in ferritin. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in IL-1beta serum parameters | Change in IL-1beta. Samples obtained through blood sampling | change month 2 from baseline | 
| Change in IL-1beta serum parameters | Change in IL-1beta. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in TNF-alpha serum parameters | Change in TNF-alpha. Samples obtained through blood sampling | change month 2 from baseline | 
| Change in TNF-alpha serum parameters | Change in TNF-alpha. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in Cytokeratin-18 serum parameters | Change in Cytokeratin-18. Samples obtained through blood sampling | change month 2 from baseline | 
| Change in Cytokeratin-18 serum parameters | Change in Cytokeratin-18. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in IL-17 serum parameters | Change in IL-17. Samples obtained through blood sampling | change month 4 from baseline | 
| Change in IL-17 serum parameters | Change in IL-17. Samples obtained through blood sampling | change month 2 from baseline | 
| Intestinal microbiota composition | Change in alpha and beta diversity of the gut microbiota as assessed by 16S bacterial gene analysis | change month 4 from baseline | 
| Change in fat values | Change in the values of total body fat and visceral fat evaluated by impedance measurement | change month 2 from baseline | 
| Change in fat values | Change in the values of total body fat and visceral fat evaluated by impedance measurement | change month 4 from baseline | 
| Change in waist values | Change in the values of waist circumference evaluated by impedance measurement | change month 2 from baseline | 
| Change in waist values | Change in the values of waist circumference evaluated by impedance measurement | change month 4 from baseline | 
| Change in waist / height index | Change in the values of waist / height index, evaluated by impedance measurement | change month 2 from baseline | 
| Change in waist / height index | Change in the values of waist / height index, evaluated by impedance measurement | change month 4 from baseline | 
| Change in hip circumference values | Change in the hip circumference evaluated by impedance measurement | change month 2 from baseline | 
| Change in hip circumference values | Change in the hip circumference evaluated by impedance measurement | change month 4 from baseline | 
| Change in BMI values | Change in the values of Body Mass Index (BMI) evaluated by impedance measurement | change month 2 from baseline | 
| Change in BMI values | Change in the values of Body Mass Index (BMI) evaluated by impedance measurement | change month 4 from baseline | 
| Adverse events | Frequency of adverse events | Throughout study completion, an average of 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NAFL, MAFL