Alcoholic Liver DiseaseSYN-ALDNCT03863730
Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota
A study testing Profermin Plus, FSMP, probiotics and Fresubin, dietary supplement in people with Alcoholic Liver Disease and Liver Cirrhosis, Alcoholic, run by Odense University Hospital at 2 sites in Denmark.
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… Read more about this study
- Who is it for?
- Ages 30 to 75 years
- Conditions the study is for
- Alcoholic Liver Disease, Liver Cirrhosis, Alcoholic, Probiotics
- What is being tested?
- Profermin Plus, FSMP, probiotics and Fresubin, dietary supplement
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 56 participants
- Where
- 2 sitesDenmark
- Study dates
- 1 Mar 2019to Feb 2031
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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)
Trial locations and contacts
2 sites in 1 country.
Denmark2 sites
FLASH - Centre of Liver Research
Odense, Fyn, 5000
Odense University Hospital
Odense, 5000
About this study
Official title: 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.
Read the 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.
- Being tested
- Profermin Plus, FSMP, probiotics, Fresubin, dietary supplement
- Keywords
- Food for special medical purposes, Gut and liver axis
- Medical subject headings
- Liver Diseases, Alcoholic, Liver Cirrhosis, Alcoholic, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Profermin Plus, FSMP, probioticsDietary supplement
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 supplementDietary supplement
Participants will have to supply their normal intake with the control product, Fresubin, dietary supplement twice every day for 24 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Profermin Plus® | Experimental | 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. Receives: Dietary Supplement: Profermin Plus, FSMP, probiotics |
| Fresubin® | Active comparator | 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. Receives: Dietary Supplement: Fresubin, dietary supplement |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 24 weeks
Secondary outcomes (28)
Hepatic a-SMA activity
Reduction in hepatic a-SMA activity
Measured: 24 weeks
Hepatic inflammation
Evaluated by hepatic inflammation markers and metabolites
Measured: 24 weeks
Alfa-smooth muscle actin concentration
Reduction in circulating a-smooth muscle actin concentration
Measured: 24 weeks
Hepatic venous pressure gradient (HVPG)
Reduction in portal pressure measured by the HVPG in unit mmhg
Measured: 24 weeks
Reduction in non-invasive fibrosis markers
Reduction in Ultrasound shear wave elastography (transient and 2-dimensional) (kPa)
Measured: 24 weeks
Reduction in non-invasive fibrosis markers
ProC3 and ProC4 (ng/ml)
Measured: 24 weeks
Reduction in non-invasive fibrosis markers
ELF test
Measured: 24 weeks
Reduction in non-invasive fibrosis markers
Forns index
Measured: 24 weeks
Reduction in non-invasive fibrosis marker
APRI score
Measured: 24 weeks
Reduction in non-invasive fibrosis markers
FIB4 (points)
Measured: 24 weeks
Markers of liver inflammation
Reduction in circulating markers of liver inflammation (cytokeratin-18 degradation products M30 and M65)
Measured: 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]
Measured: 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
Measured: 24 weeks
Liver vein outflow of microbial products
Change in Liver vein outflow of microbial products
Measured: 24 weeks
Lipid profile
Improvement of lipid profile defined as:
Rising HDL, decrease in triglycerids, LDL and total cholesterol
Measured: 24 weeks
Any changes in non-invasive markers of steatosis
Controlled Attenuation Parameter(CAP) and ultrasonographic steatosis assessment (bright liver echo pattern)
Measured: 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 (%)
Measured: 24 weeks
Metabolic changes
Water soluble metabolites in circulation will be evaluated with metabolomics
Measured: 24 weeks
Changes in circulating cytokines
Cytokines related to cardiovascular disease and inflammation will be analysed
Measured: 24 weeks
Changes in hepatic macrophage activity
Changes in digital imaging analysis of hepatic CD163 expression in liver biopsies
Measured: 24 weeks
Changes in intestinal fibrosis markers
C4M generated by decomposition of type 4 collagen
Measured: 24 weeks
Changes in intestinal fibrosis markers
CPA9-HNE a fragment degraded from calprotectin
Measured: 24 weeks
Changes bile acids
Changes in bile acids will be measured in both stool and circulation
Measured: 24 weeks
Metabolic changes
Amino acids in circulation will be evaluated with metabolomics
Measured: 24 weeks
Metabolic changes
Lipidomics in circulation will be evaluated with metabolomics
Measured: 24 weeks
Metabolic changes
Lipidomics in liver samples will be evaluated with metabolomics
Measured: 24 weeks
Metabolic changes
Short chain fatty acids in circulation will be evaluated with metabolomics
Measured: 24 weeks
Metabolic changes
Short chain fatty acids in stool samples will be evaluated with metabolomics
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2019
- Study start1 Mar 2019
- Primary completion15 Jul 2021
- Study completionFeb 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alcoholic Liver DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.
- Masking
- None (open label)
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- Odense University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Region of Southern Denmark, Odense Patient Data Explorative Network, University of Southern Denmark, Nordisk Rebalance A/S
- Responsible party
- Principal investigator, Aleksander Krag, Odense University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03863730
- Sponsor's protocol ID
- S-20170163
- Acronym
- SYN-ALD
- Status last verified
- Nov 2023
- First submitted
- 28 Feb 2019
- Last updated
- 7 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota - a Randomized Controlled Clinical Trial
- ClinicalTrials.gov ID
- NCT03863730
- Acronym / sponsor ID
- SYN-ALD / S-20170163
- Keywords
- Food for special medical purposes, Gut and liver axis
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 56 participants (actual)
- Lead sponsor
- Odense University HospitalUniversity, hospital or other
- Collaborators
- Region of Southern Denmark, Odense Patient Data Explorative Network, University of Southern Denmark, Nordisk Rebalance A/S
- Study start
- 1 Mar 2019 (actual)
- Primary completion
- 15 Jul 2021 (actual)
- Study completion
- Feb 2031 (estimated)
- First posted
- 5 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.
| Arm | Type | Receives |
|---|---|---|
| Profermin Plus® | Experimental | Dietary Supplement: Profermin Plus, FSMP, probioticsIntervention 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. |
| Fresubin® | Active comparator | Dietary Supplement: Fresubin, dietary supplementFresubin® 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. |
Who may qualify
- Ages
- 30 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Prior or ongoing harmful alcohol intake defined as an average of ≥24g alcohol/day for women and ≥36g/d for men for ≥ 5 year.
Key exclusion criteria (16 listed)
- Hospitalised
- Moderete or severe Ascites, determined from imaging diagnostics
- High-risk varices needing interventional treatment (endoscopy, TIPS)
- Child-Pugh C score
- MELD-Na ≥15
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Profermin Plus, FSMP, probioticsParticipants 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. | Dietary supplement | Profermin Plus® |
| Fresubin, dietary supplementParticipants will have to supply their normal intake with the control product, Fresubin, dietary supplement twice every day for 24 weeks. | Dietary supplement | Fresubin® |
Primary outcome
Hepatic stellate cell activity
Time frame: 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.
28 secondary outcomes
Hepatic a-SMA activity
Time frame: 24 weeks
Hepatic inflammation
Time frame: 24 weeks
Alfa-smooth muscle actin concentration
Time frame: 24 weeks
Hepatic venous pressure gradient (HVPG)
Time frame: 24 weeks
Reduction in non-invasive fibrosis markers
Time frame: 24 weeks
Reduction in non-invasive fibrosis markers
Time frame: 24 weeks
Reduction in non-invasive fibrosis markers
Time frame: 24 weeks
Reduction in non-invasive fibrosis markers
Time frame: 24 weeks
Reduction in non-invasive fibrosis marker
Time frame: 24 weeks
Reduction in non-invasive fibrosis markers
Time frame: 24 weeks
Markers of liver inflammation
Time frame: 24 weeks
Improvement of liver histological lesions
Time frame: 24 weeks
Improvement in gut dysbiosis
Time frame: 24 weeks
Liver vein outflow of microbial products
Time frame: 24 weeks
Lipid profile
Time frame: 24 weeks
Any changes in non-invasive markers of steatosis
Time frame: 24 weeks
Individual domains of NAS scoring systemt
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Changes in circulating cytokines
Time frame: 24 weeks
Changes in hepatic macrophage activity
Time frame: 24 weeks
Changes in intestinal fibrosis markers
Time frame: 24 weeks
Changes in intestinal fibrosis markers
Time frame: 24 weeks
Changes bile acids
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Metabolic changes
Time frame: 24 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Profermin Plus, FSMP, probiotics and Fresubin, dietary supplement in people with Alcoholic Liver Disease and Liver Cirrhosis, Alcoholic, run by Odense University Hospital at 2 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 7 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hepatic stellate cell activity (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2023.