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

Sponsor

Odense University Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03863730

Collaborator

Region of Southern Denmark (Other), Odense Patient Data Explorative Network (Other), University of Southern Denmark (Other), Nordisk Rebalance A/S (Industry)

Enrollment

Locations

Arms

143.1

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alcoholic Liver Disease Liver Cirrhosis, Alcoholic Probiotics Liver Fibrosis	Dietary Supplement: Profermin Plus, FSMP, probiotics Dietary Supplement: Fresubin, dietary supplement	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

56 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.

Masking:

None (Open Label)

Masking Description:

Pathologist will perform outcome assessment blinded

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Mar 1, 2019

Actual Primary Completion Date :

Jul 15, 2021

Anticipated Study Completion Date :

Feb 1, 2031

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Hepatic stellate cell activity [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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

liver stiffness ≥15 kPa and asymptomatic and/or
New liver biopsy (<6months) with at least F3 fibrosis (kleiner) and/or
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)