Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota
- Conditions
- Alcoholic Liver DiseaseLiver Cirrhosis, AlcoholicProbioticsLiver Fibrosis
- Interventions
- Dietary Supplement: Fresubin, dietary supplementDietary Supplement: Profermin Plus, FSMP, probiotics
- Registration Number
- NCT03863730
- Lead Sponsor
- Odense University Hospital
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 56
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Prior or ongoing harmful alcohol intake defined as an average of ≥24g alcohol/day for women and ≥36g/d for men for ≥ 5 year.
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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
-
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Fresubin® Fresubin, dietary supplement 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. Profermin Plus® Profermin Plus, FSMP, probiotics 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method Hepatic a-SMA activity 24 weeks Reduction in hepatic a-SMA activity
Reduction in non-invasive fibrosis markers 24 weeks FIB4 (points)
Reduction in non-invasive fibrosis marker 24 weeks APRI score
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
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 richnessMarkers of liver inflammation 24 weeks Reduction in circulating markers of liver inflammation (cytokeratin-18 degradation products M30 and M65)
Metabolic changes 24 weeks Short chain fatty acids in stool samples will be evaluated with metabolomics
Liver vein outflow of microbial products 24 weeks Change in Liver vein outflow of microbial products
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 (%)
Changes in hepatic macrophage activity 24 weeks Changes in digital imaging analysis of hepatic CD163 expression in liver biopsies
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.
\[Worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning. Resolution defined as ballooning=0 and lobular inflammation=0-1\]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
Lipid profile 24 weeks Improvement of lipid profile defined as:
Rising HDL, decrease in triglycerids, LDL and total cholesterolChanges in circulating cytokines 24 weeks Cytokines related to cardiovascular disease and inflammation will be analysed
Trial Locations
- Locations (2)
FLASH - Centre of Liver Research
🇩🇰Odense, Fyn, Denmark
Odense University Hospital
🇩🇰Odense, Denmark