The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD)

NAFLD Clinical Trial

— NAFTx  

Official title:

The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a Randomized-controlled Trial -

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04465032
• Other study ID #: GE17-05
• Status: Recruiting
• Phase: Phase 4
• Start date: December 10, 2019
• Est. completion date: December 31, 2021

Study information

• Verified date: July 2020
• Source: Leiden University Medical Center
• Contact: Maarten Tushuizen, MD PhD
• Phone: +31 71 5263541
• Email: m.e.tushuizen[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence, linked to metabolic, cardiovascular and malignant morbidity and without any officially approved treatment. It is increasingly recognized that the gut microbiome is implicated in the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides, inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The primary objective is to study the effect of consecutive FMT on liver fat accumulation measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives are weight, waist, blood pressure, metabolic parameters (including glucose, cholesterol, pancreatic beta-cell function, HOMA-IR), objective and subjective stress indicators, gut-microbiota and bile composition and liver enzymes. Stool samples will be collected for microbiota analysis at time point 0, 3, 6 and 12 weeks.

Description:

Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence, linked to metabolic, cardiovascular and malignant morbidity and without any officially approved treatment. It is increasingly recognized that the gut microbiome is implicated in the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides, inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The investigators hypothesize that altered gut microbiota underlie (hepatic) insulin resistance and liver fat accumulation in NAFLD patients. Fecal microbiota transplantation, through amelioration of gut-microbiota released products like lipopolysaccharides, short-chain fatty acids, alcohol and enzymes, and changes in bile acids, may positively affect NAFLD.

During the study 20 patients will be randomized for infusion of allogenic (lean donor) or autologous (own) feces by gastroscopy at time points 0, 3 and 6 weeks on a 1:1 basis. Prior to randomization, and at 12 weeks, all patients will undergo LiverMultiscan to non-invasively quantify liver fat accumulation and other features of NAFLD. In addition, various metabolic parameters (lipids, HOMA-IR), objective and subjective stress indicators, gut-microbiota and bile composition, and liver enzymes will be measured.

The primary objective is to study the effect on consecutive FMT on liver fat accumulation measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives are alterations in anthropometrical data (weight, waist, blood pressure), changes in fecal microbiota, liver enzymes, bile composition and metabolic parameters including glucose, lipids, pancreatic beta-cell function and insulin resistance measured as HOMA-IR and objective and subjective stress indicators.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 31, 2021
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Obese (BMI > 27 kg/m2)

• Males and postmenopausal females

• Aged 18 to 70 years

• Hepatic steatosis defined as increased hyperechogenicity of the liver on abdominal ultrasound and/or histological signs of steatosis

• Written informed consent

Exclusion Criteria:

• Exclusion criteria for MRI (claustrophobia, pacemaker, metal implants, etc)

• Any other liver disease than NAFLD/NASH

• Present excessive alcohol use defined as > 2 units/day

• Recent use (< 3 months) of antibiotics

• use of possible drugs interfering microbiota or recent (< 3 months) changes in dosages

• use of GLP-1 RA or SU-derivatives

• Recent (< 3 months) weight change (>5%)

• Cardiovascular co-morbidity defined as heart failure, coronary insufficiency and hypertension in past history

• Previous use of glucocorticosteroids, hormonal substitution, pagitaxel, theofyllin, amiodarone, myelosuppresive agents.

• A psychiatric, addictive or any other disorder that compromises the subjects ability to understand the study content and to give written informed consent for participation in the study

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• NAFLD
• Non-alcoholic Fatty Liver Disease

Intervention

Other:
• Gut microbiome transplantation
Fecal transplantation will be performed at baseline and at week 3 and 6. At the Department of Clinical Bacteriology either the autologous or allogenic feces is prepared for donation by an experienced lab co-worker. The fecal transplantation will be performed via gastroduodenal endoscopy at the Department of Gastroenterology by an experienced endoscopist. To alleviate the procedure, midazolam is offered to the participants. Following placement of the endoscope in the horizontal duodenum, 150 mL feces solution is inserted via the endoscope.

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Center	Leiden

Sponsors (3)

Lead Sponsor	Collaborator
Leiden University Medical Center	Dutch Donor Feces Bank, Vedanta Biosciences

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the effect on consecutive FMT on liver fat accumulation	measured by MRI Livermultiscan	12 weeks
Secondary	alterations in anthropometric data	differences in weight in kilograms	3, 6 and 12 weeks
Secondary	alterations in anthropometric data	differences in systolic and diastolic blood pressure in mmHg	3, 6 and 12 weeks
Secondary	alterations in anthropometric data	differences in waist in centimeters	3, 6 and 12 weeks
Secondary	alterations in pancreatic beta-cell function and insulin resistance	measured by plasma C-peptide in nmol/L derived during OGTT + arginin	3, 6 and 12 weeks
Secondary	alterations in pancreatic beta-cell function and insulin resistance	measured by glucose in mmol/L derived during OGTT + arginin	3, 6 and 12 weeks
Secondary	alterations in pancreatic beta-cell function and insulin resistance	measured by insulin in mU/L derived during OGTT + arginin	3, 6 and 12 weeks
Secondary	alterations in liver enzymes	Aspartaat aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transpeptidase (GGT), alkalic phosphatase (AF), bilirubin	3, 6 and 12 weeks
Secondary	change in bile composition	measured using endoscopic bile samples (qualitative measurements)	3 and 6 weeks
Secondary	change in bacterial species in small intestine and feces	measured by endoscopic duodenal biopsies and fecal samples	3 and 6 weeks
Secondary	changes in lipid homeostasis	cholesterol, HDL, LDL, triglycerides	3, 6 and 12 weeks
Secondary	alterations in psychological stress	by measuring cortisol levels in hair samples	0 and 12 weeks
Secondary	alterations in psychological stress	by reporting psychological stress daily using stress diaries on a scale from 1-10 (non-validated scale)	week 1, week 4, week 7, week 9 during 7 days
Secondary	alterations in psychological stress	by Perceived Stres Scale (PSS) questionnaires, scores on a scale from 0-40	0 and 12 weeks
Secondary	changes in physical activity	measuring physical activity by steps with FitBit activity tracker	during 14 weeks
Secondary	changes in physical activity	measuring physical activity by active minutes with FitBit activity tracker	during 14 weeks
Secondary	changes in physical activity	measuring physical activity by heart rate with FitBit activity tracker	during 14 weeks