Rifaximin in Fatty Liver Disease (RiFL)
Primary Purpose
Nonalcoholic Fatty Liver Disease, NAFLD, Nonalcoholic Steatohepatitis
Status
Terminated
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Rifaximin
Sponsored by
About this trial
This is an interventional treatment trial for Nonalcoholic Fatty Liver Disease focused on measuring Microbiota, Insulin resistance, Bacterial endotoxin, Hepatic triglyceride, Inflammation
Eligibility Criteria
Inclusion Criteria:
- Subject has provided written informed consent prior to screening
- Men and women aged 18-70 years
- With non-alcoholic steatohepatitis histologically-proven, as evidenced by the presence of all of: steatosis, hepatocyte ballooning and lobular inflammation, and scored according to Kleiner(18) by a single experienced histopathologist (RDG) within the previous year, with or without mild to moderate fibrosis (stage 0-3/4)
- With persistently elevated alanine aminotransferase (ALT) values on at least two occasions in the three months prior to recruitment
Exclusion Criteria:
- NAFLD with cirrhosis (fibrosis score 4)
Other causes of chronic liver disease
- Viral hepatitis (HBV, HCV negative)
- Alcohol intake >14units/week (women) or >21units/week (men)
- Haemachromatosis (abnormal transferrin saturation, haemochromatosis genotyping)
Evidence of hepatic decompensation
- Ascites
- Hepatic encephalopathy
- Abnormal total bilirubin (except patients with Gilbert's syndrome), albumin, prolonged prothrombin time, low platelets)
- Oesophageal or gastric varices
- Moderate or severe renal dysfunction (CKD3+, estimated GFR <60ml/min/1.73m2)
- Hepatocellular carcinoma
- Primary metabolic causes of hepatic steatosis (e.g. familial hypertriglyceridaemia, abetalipoproteinaemia)
- Other malignancy
- Pregnant or lactating women or women of childbearing potential unwilling/unable to use adequate contraceptive methods
Systemic inflammatory conditions
- Arthritis
- Connective tissue disorders
- Inflammatory bowel disease
- Myocardial infarction within 6 months
- Stroke within 6 months
- Bariatric surgery/ blind loop/ short bowel
- Treatment known/suspected to change gut flora (e.g. systemic antibiotics, colestyramine, lactulose, polyethylene glycol) within 3 months
- Treatment with drugs known to cause hepatic steatosis (e.g. corticosteroids, HAART, amiodarone, high dose oestrogens, tamoxifen) within 3 months
- Initiation or major dose change of metformin, thiazolidinediones, biguanides, statins, fibrates, anti-obesity medications or insulin within 3 months of enrolment
- Patients with allergy to Rifaximin or Rifamycin
- Patients with a cardiac pacemaker, history of penetrating eye injury, metal foreign body or any other contra-indication to MRI scanning, as specified in the local MRI safety checklist
- Any other clinical, social or psychological issues which, in the opinion of the investigators may preclude satisfactory completion of the study protocol
Sites / Locations
- Liver Unit, St Mary's Hospital, Imperial College London
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Rifaximin for 6-weeks followed by 6-week observation period
Arm Description
All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period.
Outcomes
Primary Outcome Measures
Serum Alanine Aminotransferase (ALT) Levels
Alanine aminotransferase (ALT) after 6-weeks of Rifaximin from baseline (end of treatment) and 12 weeks (6 weeks after end of treatment).
ALT values reported are the values from 6-weeks Rifaximin treatment compared to baseline, and ALT values from 12 weeks (after 6 weeks of SoC) compared to baseline.
Secondary Outcome Measures
Insulin Resistance
Hepatic and systemic insulin resistance assessed using the hyperinsulinaemic euglycaemic clamp method.
Measured in % Suppression of Endogenous Glucose Production (SEGP). Values reported are the value from baseline and value from 6 weeks Rifaximin treatment.
Hepatic Triglyceride Content
In vivo proton magnetic resonance spectroscopy (1H MRS) to derive a T2-corrected triglyceride to water ratio (hepatic lipid content- intra-hepatocellular lipid (IHCL)).
The values reported are the values from baseline and the values from 6 weeks Rifaximin treatment.
Full Information
NCT ID
NCT01355575
First Posted
May 17, 2011
Last Updated
October 5, 2020
Sponsor
Imperial College London
Collaborators
National Health Service, United Kingdom
1. Study Identification
Unique Protocol Identification Number
NCT01355575
Brief Title
Rifaximin in Fatty Liver Disease
Acronym
RiFL
Official Title
RiFL: Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?
Study Type
Interventional
2. Study Status
Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
Primary endpoint data review concluded no further patients required.
Study Start Date
May 2011 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
September 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
National Health Service, United Kingdom
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
TITLE Rifaximin in Fatty Liver Disease (RiFL) DESIGN Open-label pilot study HYPOTHESIS Reduction in gut flora by the antibiotic Rifaximin reduces hepatic inflammation in Non-Alcoholic Steatohepatitis (NASH).
AIMS To provide proof-of-concept data on the therapeutic potential of gut flora modification in NASH OUTCOME MEASURES
Primary:
• Change in serum ALT from baseline by 25 IU/L or to within normal range after 6 weeks of Rifaximin therapy
Secondary:
Change in intrahepatic triglyceride, estimated by in vivo proton magnetic resonance spectroscopy (1H MRS)
Change in hepatic insulin resistance, estimated by the hyperinsulinaemic euglycaemic clamp
Changes to the faecal bacterial microbiome assessed by faecal DNA pyrosequencing and fluorescent in-situ hybridisation (FISH)
Differences in urinary metabolic profiles as assessed by high-resolution proton nuclear magnetic resonance spectroscopy
POPULATION Patients with biopsy-confirmed non-alcoholic steatohepatitis and persistently raised serum aminotransferase levels
TREATMENT The non-absorbable antibiotic Rifaximin DURATION This was an open-label study of Rifaximin (Normix, Alfa Wasserman S.p.A, Bologna, Italy) 400mg twice daily for six weeks followed by a further six weeks observation period during which patients received standard care.
Detailed Description
STUDY OBJECTIVES The primary endpoint was change in ALT after 6 weeks of Rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinaemic euglycaemic clamp.
STUDY DESIGN This was an open-label study of Rifaximin (Normix, Alfa Wasserman S.p.A, Bologna, Italy) 400mg twice daily for six weeks followed by a further six weeks observation period during which patients received standard care. Compliance with treatment was checked by collection of empty blister packs. Subjects were asked to provide a structured dietary and lifestyle history as previously described (Williams HR, Cox IJ, Walker DG, North BV, Patel VM, Marshall SE, Jewell DP, et al. Characterization of inflammatory bowel disease with urinary metabolic profiling. Am J Gastroenterol 2009;104:1435-1444). The primary endpoint was change in ALT after 6 weeks' Rifaximin therapy. Secondary endpoints were change in hepatic and whole-body insulin sensitivity assessed by the two-stage hyperinsulinaemic euglycaemic clamp and change in hepatic triglyceride content assessed by proton nuclear magnetic resonance spectroscopy at 6 weeks from baseline. Serum ALT, biochemistry and anthropometrics were also measured at 12 weeks to look for longer-term effects. Stool microbiota, urinary metabolic profile and serum cytokine profile were measured before and after intervention.
PARTICIPANT ENTRY
INCLUSION CRITERIA Male and female patients were eligible for inclusion if aged between 18 and 70 years with non-alcoholic steatohepatitis histologically-proven, as evidenced by the presence of all of: steatosis, hepatocyte ballooning and lobular inflammation, and scored according to Kleiner(18) by a single experienced histopathologist (RDG) within the previous year, with or without mild to moderate fibrosis (stage 0-3/4) and with persistently elevated alanine aminotransferase (ALT) values on at least two occasions in the three months prior to recruitment.
EXCLUSION CRITERIA Patients were excluded if there was histological evidence of cirrhosis; hepatic decompensation; regular alcohol consumption exceeding 14 units/week (16g ethanol/day) for a woman or 21 units/week (24g ethanol/day) for a man; evidence of viral, autoimmune or other metabolic liver disease on a chronic liver disease screen; a history of malignancy or systemic inflammatory conditions; myocardial infarction or cerebrovascular events in the preceding 6 months; a history of bariatric surgery, blind loop or short bowel; use of any treatment known or suspected to change bowel flora within 3 months of enrolment; initiation or major dose change of metformin, thiazolinediones, biguanides, statins, fibrates, anti-obesity medications or insulin within 3 months of enrolment.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Fatty Liver Disease, NAFLD, Nonalcoholic Steatohepatitis
Keywords
Microbiota, Insulin resistance, Bacterial endotoxin, Hepatic triglyceride, Inflammation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Model Description
An open label pilot study with two phases (rather than 2 arms). All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period.
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rifaximin for 6-weeks followed by 6-week observation period
Arm Type
Experimental
Arm Description
All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period.
Intervention Type
Drug
Intervention Name(s)
Rifaximin
Other Intervention Name(s)
Xifaxan
Intervention Description
Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Primary Outcome Measure Information:
Title
Serum Alanine Aminotransferase (ALT) Levels
Description
Alanine aminotransferase (ALT) after 6-weeks of Rifaximin from baseline (end of treatment) and 12 weeks (6 weeks after end of treatment).
ALT values reported are the values from 6-weeks Rifaximin treatment compared to baseline, and ALT values from 12 weeks (after 6 weeks of SoC) compared to baseline.
Time Frame
Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment)
Secondary Outcome Measure Information:
Title
Insulin Resistance
Description
Hepatic and systemic insulin resistance assessed using the hyperinsulinaemic euglycaemic clamp method.
Measured in % Suppression of Endogenous Glucose Production (SEGP). Values reported are the value from baseline and value from 6 weeks Rifaximin treatment.
Time Frame
Baseline and 6 weeks (end of treatment)
Title
Hepatic Triglyceride Content
Description
In vivo proton magnetic resonance spectroscopy (1H MRS) to derive a T2-corrected triglyceride to water ratio (hepatic lipid content- intra-hepatocellular lipid (IHCL)).
The values reported are the values from baseline and the values from 6 weeks Rifaximin treatment.
Time Frame
Baseline and 6 weeks (end of treatment)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subject has provided written informed consent prior to screening
Men and women aged 18-70 years
With non-alcoholic steatohepatitis histologically-proven, as evidenced by the presence of all of: steatosis, hepatocyte ballooning and lobular inflammation, and scored according to Kleiner(18) by a single experienced histopathologist (RDG) within the previous year, with or without mild to moderate fibrosis (stage 0-3/4)
With persistently elevated alanine aminotransferase (ALT) values on at least two occasions in the three months prior to recruitment
Exclusion Criteria:
NAFLD with cirrhosis (fibrosis score 4)
Other causes of chronic liver disease
Viral hepatitis (HBV, HCV negative)
Alcohol intake >14units/week (women) or >21units/week (men)
Haemachromatosis (abnormal transferrin saturation, haemochromatosis genotyping)
Evidence of hepatic decompensation
Ascites
Hepatic encephalopathy
Abnormal total bilirubin (except patients with Gilbert's syndrome), albumin, prolonged prothrombin time, low platelets)
Oesophageal or gastric varices
Moderate or severe renal dysfunction (CKD3+, estimated GFR <60ml/min/1.73m2)
Hepatocellular carcinoma
Primary metabolic causes of hepatic steatosis (e.g. familial hypertriglyceridaemia, abetalipoproteinaemia)
Other malignancy
Pregnant or lactating women or women of childbearing potential unwilling/unable to use adequate contraceptive methods
Systemic inflammatory conditions
Arthritis
Connective tissue disorders
Inflammatory bowel disease
Myocardial infarction within 6 months
Stroke within 6 months
Bariatric surgery/ blind loop/ short bowel
Treatment known/suspected to change gut flora (e.g. systemic antibiotics, colestyramine, lactulose, polyethylene glycol) within 3 months
Treatment with drugs known to cause hepatic steatosis (e.g. corticosteroids, HAART, amiodarone, high dose oestrogens, tamoxifen) within 3 months
Initiation or major dose change of metformin, thiazolidinediones, biguanides, statins, fibrates, anti-obesity medications or insulin within 3 months of enrolment
Patients with allergy to Rifaximin or Rifamycin
Patients with a cardiac pacemaker, history of penetrating eye injury, metal foreign body or any other contra-indication to MRI scanning, as specified in the local MRI safety checklist
Any other clinical, social or psychological issues which, in the opinion of the investigators may preclude satisfactory completion of the study protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy FL Cobbold, PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mark R Thursz, MD
Organizational Affiliation
Imperial College London
Official's Role
Study Chair
Facility Information:
Facility Name
Liver Unit, St Mary's Hospital, Imperial College London
City
London
ZIP/Postal Code
W2 1NY
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
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Rifaximin in Fatty Liver Disease
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