A Phase 2 interventional study of Lyophilized fecal microbiota transplantation capsules and Placebo capsules in Non Alcoholic Steatohepatitis, Non-Alcoholic Fatty Liver Disease and Fecal Microbiota Transplantation, sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA). Recruiting at 1 site in Netherlands. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2024-08-27.
Sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) · Phase 2, Interventional, and Treatment
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:
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.
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.
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.
2,081 studies on the registry are indexed under Liver Diseases; 390 are open to participants now.
This study's planned enrollment of 48 is close to the median of 50 across 1,323 interventional studies indexed under Liver Diseases.
Browse Liver Diseases studies →Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) is the lead sponsor of 512 studies on the registry; 178 are open to participants now.
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Exclusion Criteria:
LFMT-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.
Combination Product: Lyophilized fecal microbiota transplantation capsules · Dietary Supplement: A. soehngenii · Dietary Supplement: Pasteurized A. muciniphila · Dietary Supplement: B. animalis subsp. lactis · Dietary Supplement: Fructo-oligosaccharides
Placebo-capsules. 3 times bulk, and further continuous administration. This arm is also treated pre- and probiotics.
Combination Product: Placebo capsules · Dietary Supplement: A. soehngenii · Dietary Supplement: Pasteurized A. muciniphila · Dietary Supplement: B. animalis subsp. lactis · Dietary Supplement: Fructo-oligosaccharides
Oral administration (capsule)
Oral administration (capsule)
Oral administration (capsule)
Oral administration (capsule)
Oral administration (capsule)
Oral administration (dissolved in water)
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.
Time frame: baseline and after 24 weeks
MRI
MRI-PDFF, MR elastography, corrected T1
Time frame: baseline and after 24 weeks
Fibroscan
CAP and LSM
Time frame: baseline and after 24 weeks
Liver enzymes (blood)
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.
Immunological data
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
Plasma lipids
plasma lipids (LDL, HDL, triglycerides, total cholesterol),
Time frame: baseline and after 24 weeks
Gut metabolites (in blood)
short chain fatty acids (i.e. propionate, butyrate, acetate), lactate, ethanol,
Time frame: baseline and after 24 weeks
Glycemic control
Continuous glucose monitoring (4x 7 consecutive days), HOMA-IR
Time frame: 5 weeks during study period
albumin, kreatinine, hemoglobin (blood)
albumin, kreatinine, hemoglobin (blood)
Time frame: baseline, 8, 16 and 24 weeks
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.
Time frame: Baseline and 24 weeks
Microbiome readouts
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.
Body weight
Body weight measured without shoes, in kilograms
Time frame: baseline and after 24 weeks
Height
Height measured without shoes, in cm
Time frame: baseline
BMI
Body mass index, calculated from height and weight kg/m\^2 (kg per meters squared)
Time frame: baseline and after 24 weeks
Waist circumference
Measured just cranial of the spina iliaca anterior superior, in cm
Time frame: baseline and after 24 weeks
Percentage body fat
Measured with a biometric device, as a percentage.
Time frame: baseline and after 24 weeks
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)
Time frame: baseline and 24 weeks
Quality of life with CDLQ-NASH
quality of life with NAFLD/NASH-specific (CDLQ-NAFLD)) questionnaire.
Time frame: baseline and after 24 weeks
Quality of life with SF36 questionnaire.
quality of life (general (SF36) questionnaire.
Time frame: baseline and after 24 weeks
Food diary
5x 10 days, daily caloric intake, daily fat and sugar consumption
Time frame: around the visits 0, 8, 16, 24 weeks
Plan to share: No
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Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)