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

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.

Full Title of Study: “Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota – a Randomized Controlled Clinical Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 15, 2021

Detailed Description

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.

Interventions

  • Dietary Supplement: Profermin Plus, FSMP, probiotics
    • 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.
  • Dietary Supplement: Fresubin, dietary supplement
    • Participants will have to supply their normal intake with the control product, Fresubin, dietary supplement twice every day for 24 weeks.

Arms, Groups and Cohorts

  • Experimental: Profermin Plus®
    • Intervention group will be drinking the liver-specialized product Profermin Plus®, based on fermented oats, Lactobacillus Plantarum 299v, barley malt and lecithin. The product also contains Thiamin, which is beneficial in patients with liver diseases.
  • Active Comparator: Fresubin®
    • Fresubin® is a standard FSMP and will be used as control product. Since Profermin Plus® is a disease-specific FSMP, the documentation must prove an effect that cannot be achieved by modification of the normal diet alone or by standard FSMP’s. Therefor the comparator must be a standard FSMP, i.e. a nutritionally complete FSMP with standard nutrient formulation, which may constitute the sole source of nourishment of a person, hence the reason for using Fresubin® as comparator.

Clinical Trial Outcome Measures

Primary Measures

  • Hepatic stellate cell activity
    • Time Frame: 24 weeks
    • 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.

Secondary Measures

  • Hepatic a-SMA activity
    • Time Frame: 24 weeks
    • Reduction in hepatic a-SMA activity
  • Hepatic inflammation
    • Time Frame: 24 weeks
    • Evaluated by hepatic inflammation markers and metabolites
  • Alfa-smooth muscle actin concentration
    • Time Frame: 24 weeks
    • Reduction in circulating a-smooth muscle actin concentration
  • Hepatic venous pressure gradient (HVPG)
    • Time Frame: 24 weeks
    • Reduction in portal pressure measured by the HVPG in unit mmhg
  • Reduction in non-invasive fibrosis markers
    • Time Frame: 24 weeks
    • Reduction in Ultrasound shear wave elastography (transient and 2-dimensional) (kPa)
  • Reduction in non-invasive fibrosis markers
    • Time Frame: 24 weeks
    • ProC3 and ProC4 (ng/ml)
  • Reduction in non-invasive fibrosis markers
    • Time Frame: 24 weeks
    • ELF test
  • Reduction in non-invasive fibrosis markers
    • Time Frame: 24 weeks
    • Forns index
  • Reduction in non-invasive fibrosis marker
    • Time Frame: 24 weeks
    • APRI score
  • Reduction in non-invasive fibrosis markers
    • Time Frame: 24 weeks
    • FIB4 (points)
  • Markers of liver inflammation
    • Time Frame: 24 weeks
    • Reduction in circulating markers of liver inflammation (cytokeratin-18 degradation products M30 and M65)
  • Improvement of liver histological lesions
    • Time Frame: 24 weeks
    • Improvement in semiquantitative liver histological lesions that fulfil at least one of two criteria: At least one stage of liver fibrosis improvement according to the Kleiner fibroses classification (0-4), with no worsening of hepatic inflammatory activity Complete resolution of hepatic inflammatory activity, with no worsening of fibrosis. [Worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning. Resolution defined as ballooning=0 and lobular inflammation=0-1]
  • Improvement in gut dysbiosis
    • Time Frame: 24 weeks
    • Defined as: Improved taxonomy, defined as increased relative abundance of species characteristic of healthy individuals and decreased relative abundance of species characteristic of cirrhosis and severe alcoholic liver disease Increase in gut microbial richness
  • Liver vein outflow of microbial products
    • Time Frame: 24 weeks
    • Change in Liver vein outflow of microbial products
  • Lipid profile
    • Time Frame: 24 weeks
    • Improvement of lipid profile defined as: Rising HDL, decrease in triglycerids, LDL and total cholesterol
  • Any changes in non-invasive markers of steatosis
    • Time Frame: 24 weeks
    • Controlled Attenuation Parameter(CAP) and ultrasonographic steatosis assessment (bright liver echo pattern)
  • Individual domains of NAS scoring systemt
    • Time Frame: 24 weeks
    • Any changes in individual domains of the NAS scoring system (fibrosis 0-4, steatosis 0-3, lobular inflammation 0-2, portal inflammation 0-1, ballooning 0-2) or in collagen proportionate area (%)
  • Metabolic changes
    • Time Frame: 24 weeks
    • Water soluble metabolites in circulation will be evaluated with metabolomics
  • Changes in circulating cytokines
    • Time Frame: 24 weeks
    • Cytokines related to cardiovascular disease and inflammation will be analysed
  • Changes in hepatic macrophage activity
    • Time Frame: 24 weeks
    • Changes in digital imaging analysis of hepatic CD163 expression in liver biopsies
  • Changes in intestinal fibrosis markers
    • Time Frame: 24 weeks
    • C4M generated by decomposition of type 4 collagen
  • Changes in intestinal fibrosis markers
    • Time Frame: 24 weeks
    • CPA9-HNE a fragment degraded from calprotectin
  • Changes bile acids
    • Time Frame: 24 weeks
    • Changes in bile acids will be measured in both stool and circulation
  • Metabolic changes
    • Time Frame: 24 weeks
    • Amino acids in circulation will be evaluated with metabolomics
  • Metabolic changes
    • Time Frame: 24 weeks
    • Lipidomics in circulation will be evaluated with metabolomics
  • Metabolic changes
    • Time Frame: 24 weeks
    • Lipidomics in liver samples will be evaluated with metabolomics
  • Metabolic changes
    • Time Frame: 24 weeks
    • Short chain fatty acids in circulation will be evaluated with metabolomics
  • Metabolic changes
    • Time Frame: 24 weeks
    • Short chain fatty acids in stool samples will be evaluated with metabolomics

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 30 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Odense University Hospital
  • Collaborator
    • Region of Southern Denmark
  • Provider of Information About this Clinical Study
    • Principal Investigator: Aleksander Krag, Professor, PhD, Cand.Med. – Odense University Hospital

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