Clinical trial NCT03863730: Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota
Official title: Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota - a Randomized Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Alcoholic Liver Disease
Liver Cirrhosis, Alcoholic
Probiotics
Liver Fibrosis
Keywords: Food for special medical purposes
Gut and liver axis
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: Region of Southern Denmark
name: Odense Patient Data Explorative Network
name: University of Southern Denmark
name: Nordisk Rebalance A/S
First posted: 2019-03-05
Enrollment: 56
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.
Primary purpose: PREVENTION

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Hepatic stellate cell activity
timeFrame: 24 weeks
Secondary outcomes:
measure: Hepatic a-SMA activity
timeFrame: 24 weeks
measure: Hepatic inflammation
timeFrame: 24 weeks
measure: Alfa-smooth muscle actin concentration
timeFrame: 24 weeks
measure: Hepatic venous pressure gradient (HVPG)
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis markers
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis markers
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis markers
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis markers
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis marker
timeFrame: 24 weeks
measure: Reduction in non-invasive fibrosis markers
timeFrame: 24 weeks
measure: Markers of liver inflammation
timeFrame: 24 weeks
measure: Improvement of liver histological lesions
timeFrame: 24 weeks
measure: Improvement in gut dysbiosis
timeFrame: 24 weeks
measure: Liver vein outflow of microbial products
timeFrame: 24 weeks
measure: Lipid profile
timeFrame: 24 weeks
measure: Any changes in non-invasive markers of steatosis
timeFrame: 24 weeks
measure: Individual domains of NAS scoring systemt
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
measure: Changes in circulating cytokines
timeFrame: 24 weeks
measure: Changes in hepatic macrophage activity
timeFrame: 24 weeks
measure: Changes in intestinal fibrosis markers
timeFrame: 24 weeks
measure: Changes in intestinal fibrosis markers
timeFrame: 24 weeks
measure: Changes bile acids
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
measure: Metabolic changes
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: FLASH - Centre of Liver Research
state: Fyn
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
References: