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Synbiotics and Fecal Microbiota Transplantation to Treat Non-Alcoholic Steatohepatitis (SYNCH)

Primary Purpose

Non Alcoholic Steatohepatitis, Non-Alcoholic Fatty Liver Disease, Fecal Microbiota Transplantation

Status
Recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
LFMT-capsules
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non Alcoholic Steatohepatitis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: biopsy-proven NASH obtained up to 32 weeks before screening: SAF Steatosis score ≥1, Activity ≥2, Fibrosis <4; 50% of participants should at least have NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on tandem reading of two expert liver pathologists fluency in Dutch or English participants should be able to understand the information and give informed consent Exclusion Criteria: Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening (significant alcohol consumption is defined as more than 2 international units/day for females and more than 3 international units/day for males, on average; 1 international unit contains ±14 grams of alcohol) liver cirrhosis or hepatocellular carcinoma hepatitis B and/or C auto-immune hepatitis Wilson's disease primary sclerosing cholangitis primary biliary cholangitis alpha-1-antitripsine deficiency and hemochromatosis history of liver transplant, current placement on a liver transplant list use of pre-, pro- or synbiotics use of systemic antibiotics 3 month prior to randomization use of tamoxifen, methotrexate or amiodarone prior or planned bariatric surgery active GLP-1 receptor agonist treated diabetes mellitus bleeding disorder International normalized ratio (INR) of prothrombin time >1.4 or platelet count <100 109/L at screening anti-platelet/coagulant therapy use which cannot be temporarily discontinued any major cardiovascular event within 6 months prior to screening (e.g. myocardial infarction, cerebrovascular accident) prolonged compromised immunity (e.g. recent cytotoxic chemotherapy, HIV-infection with a CD4 count < 240) active or prior history of invasive malignancy (except for curatively treated in situ carcinomas [e.g., cervix] or non-melanoma skin cancer) unless a complete remission was achieved surgery scheduled for the trial duration period, except for minor surgical procedures, in the opinion of the investigator pregnant or nursing women any condition which, in the investigator's opinion, might jeopardize participants' safety or compliance with the protocol participation in another concomitant clinical trial.

Sites / Locations

  • Amsterdam UMCRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

LFMT-capsules

Placebo

Arm Description

LFMT-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.

Placebo-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.

Outcomes

Primary Outcome Measures

Liver histology
Alteration of liver histology in subjects with NASH and fibrosis stage 0-3, with an alteration defined as change of steatohepatitis by ≥1 SAF-A point, or a change in ≥ 1 stage liver fibrosis.

Secondary Outcome Measures

MRI
MRI-PDFF, MR elastography, corrected T1
Fibroscan
CAP and LSM
Liver enzymes (blood)
alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP))
Immunological data
leukocytes, monocytes, CRP, Il-1(β), Il-6, Il-11, Il-17, Il-32, TNF-α, IFN-γ, other inflammatory markers),
Plasma lipids
plasma lipids (LDL, HDL, triglycerides, total cholesterol),
Gut metabolites (in blood)
short chain fatty acids (i.e. propionate, butyrate, acetate), lactate, ethanol,
Glycemic control
Continuous glucose monitoring (4x 7 consecutive days), HOMA-IR
albumin, kreatinine, hemoglobin (blood)
albumin, kreatinine, hemoglobin (blood)
NAFLD NASH related endocrinological and metabolic outcome parameters
FGF-21, adiponectin, leptin, lipopolysaccharides, estrogen, vitamin B12, folate acid, zonulin, and other metabolomic and lipidomic outcomes.
Microbiome readouts
microbiome read outs (composition, engraftment, strain tracking) and metabolites, fecal SCFA-composition, and fecal albumine.
Body weight
Body weight measured without shoes, in kilograms
Height
Height measured without shoes, in cm
BMI
Body mass index, calculated from height and weight kg/m^2 (kg per meters squared)
Waist circumference
Measured just cranial of the spina iliaca anterior superior, in cm
Percentage body fat
Measured with a biometric device, as a percentage.
Demographics and (medical) history
Sex, age, ethnicity, height, weight, comorbidities (e.g. diabetes), smoking, alcohol intake, medication use, polypharmacy (defined as chronic use of ≥ 5 different medications)
Quality of life with CDLQ-NASH
quality of life with NAFLD/NASH-specific (CDLQ-NAFLD)) questionnaire.
Quality of life with SF36 questionnaire.
quality of life (general (SF36) questionnaire.
Food diary
5x 10 days, daily caloric intake, daily fat and sugar consumption

Full Information

First Posted
March 8, 2023
Last Updated
April 6, 2023
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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1. Study Identification

Unique Protocol Identification Number
NCT05821010
Brief Title
Synbiotics and Fecal Microbiota Transplantation to Treat Non-Alcoholic Steatohepatitis
Acronym
SYNCH
Official Title
Synbiotics and Fecal Microbiota Transplantation to Treat Non-Alcoholic Steatohepatitis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 17, 2023 (Actual)
Primary Completion Date
February 20, 2025 (Anticipated)
Study Completion Date
August 20, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to investigate the therapeutic potential of A. soehngenii and pasteurized A. muciniphila combined with B. animalis subsp. lactis and fructo-oligosaccharides with and without conditioned vegan lyophilized fecal microbiota transplantation capsules to reduce NASH in patients with fibrotic NASH. The main questions to answer are: Can NASH be treated by altering the gut microbiota using LFMT capsules? Can NASH be treated using a syntrophic cocktail of synbiotics and will these strains strengthen the effect of FMT? What are the underlying mechanism by which the aforementioned treatments attenuate NASH? Participants will be treated with FMT-capsules or placebo, and all participants will receive a cocktail of 3 strains of probiotics and one type of prebiotic.
Detailed Description
Main objective To investigate the therapeutic potential of A. soehngenii and pasteurized A. muciniphila combined with B. animalis subsp. lactis and fructo-oligosaccharides with and without conditioned vegan lyophilized fecal microbiota transplantation (LFMT) capsules to reduce NASH in patients with NASH and NASH-fibrosis. Secondary objective To investigate the mechanisms of A. soehngenii and pasteurized A. muciniphila combined with B. animalis subsp. lactis and FOS with and without conditioned vegan LFMT capsules in reducing NASH in patients with NASH and NASH-fibrosis. Study design: Double-blind randomized placebo-controlled intervention study. Study population: Patients between age 18-75 years with biopsy-proven NASH obtained up to 32 weeks before screening based on tandem reading of two expert liver pathologists: SAF Steatosis score ≥1, Activity ≥2, Fibrosis <4; 50% of participants should at least have NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system. Exclusion criteria are: Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening (significant alcohol consumption is defined as more than 2 units/day for females and more than 3 international units/day for males, on average; 1 international unit contains ±14 grams of alcohol), liver cirrhosis or hepatocellular carcinoma, hepatitis B and/or C, auto-immune hepatitis, Wilson's disease, primary sclerosing cholangitis, primary biliary cholangitis, alpha-1-antitripsine deficiency and hemochromatosis, history of liver transplant, current placement on a liver transplant list, use of pre-, pro- or synbiotics, use of systemic antibiotics 3 month prior to randomization, use of tamoxifen, methotrexate or amiodarone, prior or planned bariatric surgery, diabetes mellitus with active GLP-1 receptor agonist treatment, bleeding disorder, International normalized ratio (INR) of prothrombin time >1.4 or platelet count <50 109/L at screening, anti-platelet/coagulant therapy use which cannot be temporarily discontinued, any major cardiovascular event within 6 months prior to screening (e.g. myocardial infarction, cerebrovascular accident), prolonged compromised immunity (e.g. recent cytotoxic chemotherapy, HIV-infection with a CD4 count < 240), active or prior history of invasive malignancy (except for curatively treated in situ carcinomas [e.g., cervix] or non-melanoma skin cancer) unless a complete remission was achieved, surgery scheduled for the trial duration period, except for minor surgical procedures in the opinion of the investigator, pregnant or nursing women, any condition which, in the investigator's opinion, might jeopardize participants' safety or compliance with the protocol, and participation in another concomitant clinical trial. A total of 48 patients will receive synbiotic treatment with A. soehngenii, pasteurized A. muciniphila, B. animalis subsp. lactis and fructo-oligosaccharides, and will be randomized 1:1 to treatment with FMT or placebo, stratified for proton-pump inhibitor use, metformin use, and histopathological fibrosis score. Intervention: Recipient participants From day -3 before the first FMT until completion of the study, all recipient participants will receive an oral daily single dose of 5 g FOS. Subsequently, participants will be randomized to lean donor FMT capsules (donors conditioned with WholeFiber) or placebo (blinded design)1. At baseline (day 0) and at week 8 (day 56) and week 16 (day 112) participants will ingest 21 LFMT or placebo capsules. The study visits will be 8 weeks apart, although a margin of -3 days to +3 days is implemented to take participants schedule and availability into account. In addition, participants will daily take 2 capsules of LFMT or placebo during the whole study period (24 weeks). The investigators have previously observed that gut microbiota composition in the recipient is affected up to 8-12 weeks after donor FMT1, so this time window ensures a stable donor gut microbiota composition during the study. During the 24-week intervention period, all participants will take daily doses of 109 A. soehngenii CH-106 cells (dosage based on previous studies including toxicology study)2,3, 1010 B. animalis subsp. lactis BLC1 (a well-studied strain marketed as a probiotic by Sacco SRL) and 3x1010 pasteurized A. muciniphila ATCC BAA-835T cells (dosage based on EFSA approval and obtained from A-Mansia Biotech). Percutaneous liver biopsies will be performed as a part of screening when participants are theoretically eligible for participation, unless a liver biopsy has been performed in the previous 36 weeks. A tandem-read by two liver pathologists blinded to any other result will determine if patients will be included in the study. At 24 weeks, another liver biopsy will be performed to examine the effect of the FMT, which will also be reviewed by two liver pathologists (again blinded to any other result). The NASH-CRN classification will be assessed on H&E slides, for steatosis, inflammation and ballooning, and with a Sirius red-stained slide for evaluation of fibrosis. RNA for RNA-sequencing will be isolated. Differential gene expression will be assessed over time (baseline and 24 weeks) and by treatment allocation (vegan donor FMT versus placebo). Feces will be collected at baseline, and after week 2, 8, 10, 16, 18, and 24, in order to investigate the changes in gut microbiome. Also, markers of gut barrier function will be assessed. Blood will be collected at baseline and at 8, 16 and 24 weeks to investigate common liver enzymes, indicators of glycemic control, lipids, and general and more NASH-specific inflammation parameters. A multiparametric MRI of liver (MRI-PDFF, MR elastography, corrected T1) and of visceral and subcutaneous fat will be performed at baseline and after 24 weeks to estimate visceral and subcutaneous adipose tissue depot volume, hepatic fat content as well as hepatic fibrosis and inflammation. Continuous glucose measurements will be performed at home using portable devices, during a consecutive period of 1 week (7 days) in the week before baseline, week 1, 9, 17 and 25. Vegan donors The fecal donor samples will be collected, lyophilized ('freeze-dried'), and encapsulated (see paragraph 6.8). Thereafter, the LFMT capsules will be stored at -80°C. Donors will be extensively screened for infectious diseases. Primary outcome To demonstrate that A. soehngenii combined with pasteurized A. muciniphila and B. animalis subsp. lactis, FOS and conditioned vegan LFMT capsules reduce NASH as defined by an improvement of liver histology in individuals with NASH and fibrosis stage 0-3, with improvement defined as reduction of steatohepatitis by ≥1 SAF-A point and no worsening of liver fibrosis, or improvement in ≥ 1 stage liver fibrosis and no worsening of steatohepatitis. Secondary outcomes To demonstrate that the combined treatment improves: non-invasive outcomes of NAFLD, i.e. multiparametric MRI of liver and surrounding subcutaneous adipose tissue (MRI-PDFF, MR elastography, corrected T1), FibroScan Elastography and Controlled Attenuation Parameters, and plasma panel Enhanced Liver Fibrosis (ELF) panel, pro-C3. change in blood markers from baseline to end of treatment, namely: liver enzymes (i.e. alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP)), inflammatory blood markers (i.e. leukocytes, monocytes, CRP, Il-1(β), Il-6, Il-11, Il-17, Il-32, TNF-α, IFN-γ, other inflammatory markers), SCFA (i.e. propionate, butyrate, acetate), lactate, ethanol, plasma lipids (i.e. LDL, HDL, triglycerides, total cholesterol), albumin, kreatinine, hemoglobin, FGF-21, adiponectin, leptin, lipopolysaccharides, estrogen, vitamin B12, folate acid,zonulin, and other metabolomic and lipodomic outcomes. microbiome read outs (composition, engraftment, strain tracking) and metabolites, fecal SCFA-composition, and fecal albumine. glycemic control, insulin resistance, body weight/BMI, waist circumference and percentage body fat MetSy criteria / % SCFA production and GLP1 release liver gene expression profile: lipogenic, inflammatory and fibrogenic pathways. liver pathology, histopathological features, immunofluorescence and assessment of pathophysiological proteins. NAFLD histology as assessed with a deep-learned algorithm scoring whole slide images of liver biopsies. Continuous glucose monitoring (4x 7 consecutive days) quality of life (general (SF36) and NAFLD/NASH-specific (CDLQ-NAFLD)).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non Alcoholic Steatohepatitis, Non-Alcoholic Fatty Liver Disease, Fecal Microbiota Transplantation, FMT, Prebiotics, Probiotics, Microbiome, Intestinal Microbiome, Gut Microbiome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized placebo-controlled trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Doubleblind
Allocation
Randomized
Enrollment
48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
LFMT-capsules
Arm Type
Experimental
Arm Description
LFMT-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.
Intervention Type
Combination Product
Intervention Name(s)
LFMT-capsules
Other Intervention Name(s)
A. soehngenii, Pasteurized A. muciniphila, B. animalis subsp. lactis, Fructo-oligosaccharides
Intervention Description
Lyophilized fecal microbiota transplantation capsules
Primary Outcome Measure Information:
Title
Liver histology
Description
Alteration of liver histology in subjects with NASH and fibrosis stage 0-3, with an alteration defined as change of steatohepatitis by ≥1 SAF-A point, or a change in ≥ 1 stage liver fibrosis.
Time Frame
baseline and after 24 weeks
Secondary Outcome Measure Information:
Title
MRI
Description
MRI-PDFF, MR elastography, corrected T1
Time Frame
baseline and after 24 weeks
Title
Fibroscan
Description
CAP and LSM
Time Frame
baseline and after 24 weeks
Title
Liver enzymes (blood)
Description
alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP))
Time Frame
baseline and after 24 weeks; 8 and 16 weeks for safety.
Title
Immunological data
Description
leukocytes, monocytes, CRP, Il-1(β), Il-6, Il-11, Il-17, Il-32, TNF-α, IFN-γ, other inflammatory markers),
Time Frame
baseline and after 24 weeks
Title
Plasma lipids
Description
plasma lipids (LDL, HDL, triglycerides, total cholesterol),
Time Frame
baseline and after 24 weeks
Title
Gut metabolites (in blood)
Description
short chain fatty acids (i.e. propionate, butyrate, acetate), lactate, ethanol,
Time Frame
baseline and after 24 weeks
Title
Glycemic control
Description
Continuous glucose monitoring (4x 7 consecutive days), HOMA-IR
Time Frame
5 weeks during study period
Title
albumin, kreatinine, hemoglobin (blood)
Description
albumin, kreatinine, hemoglobin (blood)
Time Frame
baseline, 8, 16 and 24 weeks
Title
NAFLD NASH related endocrinological and metabolic outcome parameters
Description
FGF-21, adiponectin, leptin, lipopolysaccharides, estrogen, vitamin B12, folate acid, zonulin, and other metabolomic and lipidomic outcomes.
Time Frame
Baseline and 24 weeks
Title
Microbiome readouts
Description
microbiome read outs (composition, engraftment, strain tracking) and metabolites, fecal SCFA-composition, and fecal albumine.
Time Frame
baseline and after 24 weeks, and 5 times in between.
Title
Body weight
Description
Body weight measured without shoes, in kilograms
Time Frame
baseline and after 24 weeks
Title
Height
Description
Height measured without shoes, in cm
Time Frame
baseline
Title
BMI
Description
Body mass index, calculated from height and weight kg/m^2 (kg per meters squared)
Time Frame
baseline and after 24 weeks
Title
Waist circumference
Description
Measured just cranial of the spina iliaca anterior superior, in cm
Time Frame
baseline and after 24 weeks
Title
Percentage body fat
Description
Measured with a biometric device, as a percentage.
Time Frame
baseline and after 24 weeks
Title
Demographics and (medical) history
Description
Sex, age, ethnicity, height, weight, comorbidities (e.g. diabetes), smoking, alcohol intake, medication use, polypharmacy (defined as chronic use of ≥ 5 different medications)
Time Frame
baseline and 24 weeks
Title
Quality of life with CDLQ-NASH
Description
quality of life with NAFLD/NASH-specific (CDLQ-NAFLD)) questionnaire.
Time Frame
baseline and after 24 weeks
Title
Quality of life with SF36 questionnaire.
Description
quality of life (general (SF36) questionnaire.
Time Frame
baseline and after 24 weeks
Title
Food diary
Description
5x 10 days, daily caloric intake, daily fat and sugar consumption
Time Frame
around the visits 0, 8, 16, 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: biopsy-proven NASH obtained up to 32 weeks before screening: SAF Steatosis score ≥1, Activity ≥2, Fibrosis <4; 50% of participants should at least have NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on tandem reading of two expert liver pathologists fluency in Dutch or English participants should be able to understand the information and give informed consent Exclusion Criteria: Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening (significant alcohol consumption is defined as more than 2 international units/day for females and more than 3 international units/day for males, on average; 1 international unit contains ±14 grams of alcohol) liver cirrhosis or hepatocellular carcinoma hepatitis B and/or C auto-immune hepatitis Wilson's disease primary sclerosing cholangitis primary biliary cholangitis alpha-1-antitripsine deficiency and hemochromatosis history of liver transplant, current placement on a liver transplant list use of pre-, pro- or synbiotics use of systemic antibiotics 3 month prior to randomization use of tamoxifen, methotrexate or amiodarone prior or planned bariatric surgery active GLP-1 receptor agonist treated diabetes mellitus bleeding disorder International normalized ratio (INR) of prothrombin time >1.4 or platelet count <100 109/L at screening anti-platelet/coagulant therapy use which cannot be temporarily discontinued any major cardiovascular event within 6 months prior to screening (e.g. myocardial infarction, cerebrovascular accident) prolonged compromised immunity (e.g. recent cytotoxic chemotherapy, HIV-infection with a CD4 count < 240) active or prior history of invasive malignancy (except for curatively treated in situ carcinomas [e.g., cervix] or non-melanoma skin cancer) unless a complete remission was achieved surgery scheduled for the trial duration period, except for minor surgical procedures, in the opinion of the investigator pregnant or nursing women any condition which, in the investigator's opinion, might jeopardize participants' safety or compliance with the protocol participation in another concomitant clinical trial.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Quinten Augustijn, MD
Phone
+31205661267
Email
q.j.augustijn@amsterdamumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
A.G. Holleboom, MD, PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amsterdam UMC
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1105AZ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Q.J.J. Augustijn, MD
Phone
+315661267
Email
q.j.augustijn@amsterdamumc.nl

12. IPD Sharing Statement

Plan to Share IPD
No

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Synbiotics and Fecal Microbiota Transplantation to Treat Non-Alcoholic Steatohepatitis

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