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

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ClinicalTrials.gov Identifier: NCT04465032
Recruitment Status : Recruiting
First Posted : July 9, 2020
Last Update Posted : July 9, 2020
Sponsor:
Collaborators:
Dutch Donor Feces Bank
Vedanta Biosciences
Information provided by (Responsible Party):
metushuizen, Leiden University Medical Center

Brief 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.

Condition or disease Intervention/treatment Phase
NAFLD Other: Gut microbiome transplantation Phase 4

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blinded randomized controlled trial, randomization 1:1 to allogenic and autologous gut microbiome transplantation
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blinded RCT, randomization by Dutch Donor Feces Bank
Primary Purpose: Treatment
Official Title: The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a Randomized-controlled Trial -
Actual Study Start Date : December 10, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Active Comparator: Autologous gut microbiome transplantation
Three autologous (own) fecal transplantations (at baseline, 3 and 6 weeks)
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.
Other Name: Fecal transplantation

Experimental: Allogenic gut microbiome transplantation
Three allogenic (lean donor) fecal transplantations (at baseline, 3 and 6 weeks)
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.
Other Name: Fecal transplantation




Primary Outcome Measures :
  1. the effect on consecutive FMT on liver fat accumulation [ Time Frame: 12 weeks ]
    measured by MRI Livermultiscan


Secondary Outcome Measures :
  1. alterations in anthropometric data [ Time Frame: 3, 6 and 12 weeks ]
    differences in weight in kilograms

  2. alterations in anthropometric data [ Time Frame: 3, 6 and 12 weeks ]
    differences in systolic and diastolic blood pressure in mmHg

  3. alterations in anthropometric data [ Time Frame: 3, 6 and 12 weeks ]
    differences in waist in centimeters

  4. alterations in pancreatic beta-cell function and insulin resistance [ Time Frame: 3, 6 and 12 weeks ]
    measured by plasma C-peptide in nmol/L derived during OGTT + arginin

  5. alterations in pancreatic beta-cell function and insulin resistance [ Time Frame: 3, 6 and 12 weeks ]
    measured by glucose in mmol/L derived during OGTT + arginin

  6. alterations in pancreatic beta-cell function and insulin resistance [ Time Frame: 3, 6 and 12 weeks ]
    measured by insulin in mU/L derived during OGTT + arginin

  7. alterations in liver enzymes [ Time Frame: 3, 6 and 12 weeks ]
    Aspartaat aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transpeptidase (GGT), alkalic phosphatase (AF), bilirubin

  8. change in bile composition [ Time Frame: 3 and 6 weeks ]
    measured using endoscopic bile samples (qualitative measurements)

  9. change in bacterial species in small intestine and feces [ Time Frame: 3 and 6 weeks ]
    measured by endoscopic duodenal biopsies and fecal samples

  10. changes in lipid homeostasis [ Time Frame: 3, 6 and 12 weeks ]
    cholesterol, HDL, LDL, triglycerides

  11. alterations in psychological stress [ Time Frame: 0 and 12 weeks ]
    by measuring cortisol levels in hair samples

  12. alterations in psychological stress [ Time Frame: week 1, week 4, week 7, week 9 during 7 days ]
    by reporting psychological stress daily using stress diaries on a scale from 1-10 (non-validated scale)

  13. alterations in psychological stress [ Time Frame: 0 and 12 weeks ]
    by Perceived Stres Scale (PSS) questionnaires, scores on a scale from 0-40

  14. changes in physical activity [ Time Frame: during 14 weeks ]
    measuring physical activity by steps with FitBit activity tracker

  15. changes in physical activity [ Time Frame: during 14 weeks ]
    measuring physical activity by active minutes with FitBit activity tracker

  16. changes in physical activity [ Time Frame: during 14 weeks ]
    measuring physical activity by heart rate with FitBit activity tracker



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04465032


Contacts
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Contact: Maarten Tushuizen, MD PhD +31 71 5263541 m.e.tushuizen@lumc.nl

Locations
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Netherlands
Leiden University Medical Center Recruiting
Leiden, Netherlands, 2333 ZA
Contact: Maarten Tushuizen, MD, PhD       m.e.tushuizen@lumc.nl   
Contact: Merel Ruissen, MD       m.m.ruissen@lumc.nl   
Sponsors and Collaborators
Leiden University Medical Center
Dutch Donor Feces Bank
Vedanta Biosciences
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Responsible Party: metushuizen, Principle investigator, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT04465032    
Other Study ID Numbers: GE17-05
First Posted: July 9, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases