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

Liver Fibrosis Clinical Trial

— SYN-ALD  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03863730
• Other study ID #: S-20170163
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 1, 2019
• Est. completion date: February 2031

Study information

• Verified date: November 2023
• Source: Odense University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 56
• Est. completion date: February 2031
• Est. primary completion date: July 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 75 Years

Eligibility

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)

Related Conditions & MeSH terms

• Alcoholic Liver Disease
• Liver Cirrhosis
• Liver Cirrhosis, Alcoholic
• Liver Diseases
• Liver Diseases, Alcoholic
• Liver Fibrosis
• Probiotics

Intervention

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

Locations

Country	Name	City	State
Denmark	FLASH - Centre of Liver Research	Odense	Fyn
Denmark	Odense University Hospital	Odense

Sponsors (5)

Lead Sponsor	Collaborator
Odense University Hospital	Nordisk Rebalance A/S, Odense Patient Data Explorative Network, Region of Southern Denmark, University of Southern Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

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