Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota

N/AActive Not RecruitingNCT03863730

Odense University Hospital56 enrolled

Overview

Investigators wishes to influence the gut microbiota in patients with alcoholic liver disease in a randomized controlled clinical trial. The investigators hypothesize that the alcohol-related dysbiosis seen in these patients can be changed and disease progression haltered by modulating microbiota with probiotics during 24 weeks.

Chronic alcohol overuse is associated with increased gut permeability and in addition, the intestinal microbiota changes qualitatively (dysbiosis) and quantitatively (bacterial overgrowth) in alcoholic liver disease in favour of a microbiota with increased invasive potential. As a consequence, an increased load of bacterial products is transported to the liver leading to inflammation and fibrogenesis. This cross talk between the intestinal microbiota and the liver constitute a gut-liver axis, which is increasingly recognized as key mechanism in the progression of liver disease and pathogenesis of liver related complications. The investigators hypothesize that the gut microbiota and its metabolites are major drivers of fibrosis in human liver disease and that modulating the intestinal flora by Profermin® (a food for special medical purposes) will modulate the alcohol related dysbiotic signatures in the microbiota which may halter disease progression by reducing activity of hepatic stellate cells. Dietary supplements that alter the microbiome towards a more beneficent type may improve liver inflammation and thus be a better alternative than supplements that simply add nutrients. Investigators expect that the trial will provide proof-of-concept for a sustainable dietary strategy in liver fibrosis. Examples of biopsies which did not meet quality criteria for reliable histological reading, led to inclusion of 16 extra patients. In total we included 56 patients to ensure an adequate number of participants with valid liver biopsy data for assessment of the primary endpoint and intention-to-treat analysis.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Conditions

Alcoholic Liver Disease Liver Cirrhosis, Alcoholic Probiotics Liver Fibrosis

Interventions

Profermin Plus, FSMP, probioticsDIETARY_SUPPLEMENT

Participants will have to supply their normal intake with Profermin Plus, FSMP, Prbiotics product twice every day for 24 weeks. The product Profermin Plus® has changed its name to ReFerm®. The content of the product is unchanged. The change occurred after the clinical part of the study was completed.

Fresubin, dietary supplementDIETARY_SUPPLEMENT

Participants will have to supply their normal intake with the control product, Fresubin, dietary supplement twice every day for 24 weeks.

Eligibility

Sex: ALLMin age: 30 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Prior or ongoing harmful alcohol intake defined as an average of ≥24g alcohol/day for women and ≥36g/d for men for ≥ 5 year. * Outpatients with compensated advanced chronic alcohol-related liver disease, defined as stable patients with: 1. liver stiffness ≥15 kPa and asymptomatic and/or 2. New liver biopsy (\<6months) with at least F3 fibrosis (kleiner) and/or 3. Liver biopsy older that 6 months with liver stiffness ≥10 kPa * Understand and speak Danish written and orally * Informed consent Exclusion Criteria: * Hospitalised * Moderete or severe Ascites, determined from imaging diagnostics * High-risk varices needing interventional treatment (endoscopy, TIPS) * Child-Pugh C score * MELD-Na ≥15 * Lactose intolerance * Coeliac disease * Irritable bowel syndrome defined by ROME III criteria * Antibiotic treatment the prior 3 months * Treatment with nutritional drinks, probiotics or prebiotics within the last 3 months * The investigator judge that the patient would not be compliant with trial medicine * Pregnancy * Known liver disease other than alcoholic, of any aetiology * Severe malnutrition * Malignancy - except spino- or basocellular skin cancer. Patients with prior malignant disease are allowed if cancer-free for at least one year * Recent infectious gastroenteritis (for the last 6 weeks)

Locations (2)

FLASH - Centre of Liver Research

Odense, Fyn, Denmark

Odense University Hospital

Odense, Denmark

Outcomes

Primary Outcomes

Hepatic stellate cell activity

Attenuation of liver hepatic stellate cell activity, defined as the proportion of patients with a 10% or more reduction in activated hepatic stellate cells, measured by a-smooth muscle actin (a-SMA) stain quantification of liver biopsies.

Time frame: 24 weeks

Secondary Outcomes

Hepatic a-SMA activity

Reduction in hepatic a-SMA activity

Time frame: 24 weeks

Hepatic inflammation

Evaluated by hepatic inflammation markers and metabolites

Time frame: 24 weeks

Alfa-smooth muscle actin concentration

Reduction in circulating a-smooth muscle actin concentration

Time frame: 24 weeks

Hepatic venous pressure gradient (HVPG)

Reduction in portal pressure measured by the HVPG in unit mmhg

Time frame: 24 weeks

Reduction in non-invasive fibrosis markers

Reduction in Ultrasound shear wave elastography (transient and 2-dimensional) (kPa)

Time frame: 24 weeks

Reduction in non-invasive fibrosis markers

ProC3 and ProC4 (ng/ml)

Time frame: 24 weeks

Reduction in non-invasive fibrosis markers

ELF test

Time frame: 24 weeks

Data from ClinicalTrials.gov

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