Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota (SYN-ALD)

Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota - a Randomized Controlled Clinical Trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Probiotics; Liver Fibrosis; Alcoholic Liver Disease; Liver Cirrhosis, Alcoholic
• Intervention / Treatment: Dietary supplement: Profermin Plus, FSMP, probiotics; Dietary supplement: Fresubin, dietary supplement

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Odense University Hospital
  • Fyn
    • Odense, Fyn, Denmark, 5000
      • FLASH - Centre of Liver Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic a-SMA activity	Reduction in hepatic a-SMA activity	24 weeks
Hepatic inflammation	Evaluated by hepatic inflammation markers and metabolites	24 weeks
Alfa-smooth muscle actin concentration	Reduction in circulating a-smooth muscle actin concentration	24 weeks
Hepatic venous pressure gradient (HVPG)	Reduction in portal pressure measured by the HVPG in unit mmhg	24 weeks
Reduction in non-invasive fibrosis markers	Reduction in Ultrasound shear wave elastography (transient and 2-dimensional) (kPa)	24 weeks
Reduction in non-invasive fibrosis markers	ProC3 and ProC4 (ng/ml)	24 weeks
Reduction in non-invasive fibrosis markers	ELF test	24 weeks
Reduction in non-invasive fibrosis markers	Forns index	24 weeks
Reduction in non-invasive fibrosis marker	APRI score	24 weeks
Reduction in non-invasive fibrosis markers	FIB4 (points)	24 weeks
Markers of liver inflammation	Reduction in circulating markers of liver inflammation (cytokeratin-18 degradation products M30 and M65)	24 weeks
Improvement of liver histological lesions	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]	24 weeks
Improvement in gut dysbiosis	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	24 weeks
Liver vein outflow of microbial products	Change in Liver vein outflow of microbial products	24 weeks
Lipid profile	Improvement of lipid profile defined as: Rising HDL, decrease in triglycerids, LDL and total cholesterol	24 weeks
Any changes in non-invasive markers of steatosis	Controlled Attenuation Parameter(CAP) and ultrasonographic steatosis assessment (bright liver echo pattern)	24 weeks
Individual domains of NAS scoring systemt	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 (%)	24 weeks
Metabolic changes	Water soluble metabolites in circulation will be evaluated with metabolomics	24 weeks
Changes in circulating cytokines	Cytokines related to cardiovascular disease and inflammation will be analysed	24 weeks
Changes in hepatic macrophage activity	Changes in digital imaging analysis of hepatic CD163 expression in liver biopsies	24 weeks
Changes in intestinal fibrosis markers	C4M generated by decomposition of type 4 collagen	24 weeks
Changes in intestinal fibrosis markers	CPA9-HNE a fragment degraded from calprotectin	24 weeks
Changes bile acids	Changes in bile acids will be measured in both stool and circulation	24 weeks
Metabolic changes	Amino acids in circulation will be evaluated with metabolomics	24 weeks
Metabolic changes	Lipidomics in circulation will be evaluated with metabolomics	24 weeks
Metabolic changes	Lipidomics in liver samples will be evaluated with metabolomics	24 weeks
Metabolic changes	Short chain fatty acids in circulation will be evaluated with metabolomics	24 weeks
Metabolic changes	Short chain fatty acids in stool samples will be evaluated with metabolomics	24 weeks

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: University of Southern Denmark; Region of Southern Denmark; Odense Patient Data Explorative Network; Nordisk Rebalance A/S

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): July 15, 2021
• Study Completion (Estimated): February 1, 2031

Study Registration Dates

• First Submitted: February 28, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 4, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Food for special medical purposes; Gut and liver axis
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Pathologic Processes; Alcohol-Related Disorders; Substance-Related Disorders; Fibrosis; Alcohol-Induced Disorders; Liver Diseases; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Cirrhosis, Alcoholic
• Other Study ID Numbers: S-20170163

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No