Rifaximin in Fatty Liver Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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RiFL: Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?

Conditions
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Nonalcoholic Fatty Liver Disease, NAFLD, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Rifaximin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin for 6-weeks followed by 6-week observation period<br>All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period. | Drug: Rifaximin<br>* Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.<br>* Other names: Xifaxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 6 weeks (end of 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. | Baseline and 6 weeks (end of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiota, Insulin resistance, Bacterial endotoxin, Hepatic triglyceride, Inflammation