Rifaximin in Fatty Liver Disease
Condition: Nonalcoholic Fatty Liver Disease; NAFLD; Nonalcoholic Steatohepatitis
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Rifaximin
Intervention description: Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Intervention MeSH terms: Rifaximin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention 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)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Microbiota; Insulin resistance; Bacterial endotoxin; Hepatic triglyceride; Inflammation

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.
    

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