Rifaximin in Fatty Liver Disease (RiFL)

This study has been terminated.
(Review of primary endpoint data by study Investigators concluded no further patients required.)
Sponsor:
Collaborator:
National Health Service, United Kingdom
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01355575
First received: May 17, 2011
Last updated: October 16, 2012
Last verified: October 2012
  Purpose

TITLE Rifaximin in Fatty Liver Disease (RiFL) DESIGN Proof-of-principle, open-label, randomised, cross-over, controlled 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 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 Study duration 18 months. Individual patients' participation 18 weeks, with clinical follow-up 3 months after the end of the study.


Condition Intervention Phase
Nonalcoholic Fatty Liver Disease
NAFLD
Nonalcoholic Steatohepatitis
Drug: Rifaximin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: RiFL:Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Change in serum ALT levels [ Time Frame: 6 weeks therapy ] [ Designated as safety issue: No ]
    ALT value at timepoint post-therapy phase (6 weeks or 12 weeks) minus ALT value pre-therapy phase (0 weeks or 6 weeks)


Secondary Outcome Measures:
  • Change in insulin resistance [ Time Frame: 6 weeks of therapy ] [ Designated as safety issue: No ]
    Hepatic and systemic insulin resistance assessed using the hyperinsulinaemic euglycaemic clamp method

  • Change in hepatic triglyceride content [ Time Frame: 6 weeks of therapy ] [ Designated as safety issue: No ]
    In vivo proton magnetic resonance spectroscopy (1H MRS) to derive a T2-corrected triglyceride to water ratio


Enrollment: 15
Study Start Date: May 2011
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: Rifaximin first then standard care
Rifaximin for 6 weeks in addition to standard care, followed by 12 weeks of standard care only.
Drug: Rifaximin
Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Experimental: B: Standard care first then Rifaximin
Standard care for 6 weeks then Rifaximin for 6 weeks in addition to standard care, followed by 6 weeks of standard care only.
Drug: Rifaximin
Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.

  Hide Detailed Description

Detailed Description:

STUDY OBJECTIVES

Hypothesis: Reduction in gut flora by the antibiotic Rifaximin reduces hepatic inflammation in non-alcoholic steatohepatitis (NASH).

Objectives:

Primary: - To assess whether the endoluminal antimicrobial properties of Rifaximin lead to changes in hepatocellular inflammation in NASH Secondary:- To determine whether Rifaximin's effect on bowel flora leads to: altered cytokine profile, decreased insulin resistance and reduced hepatic steatosis

- To corroborate previously identified urinary markers of non-alcoholic fatty liver disease associated with bacterial choline metabolism using urinary proton nuclear magnetic resonance spectroscopy

STUDY DESIGN

A proof-of-concept open-label randomized controlled cross-over interventional cohort study.

Twenty four patients with biopsy-proven mild to moderate NASH will be recruited prospectively over 9 months and assessed at four time-points after the screening visit: baseline; 6 weeks; 12 weeks and 18 weeks. Participants will be randomized to receive either Rifaximin 400mg twice a day for 6 weeks then standard of care (SoC) for 6 weeks, or SoC for 6 weeks then Rifaximin 400mg twice a day for 6 weeks, all undergoing a 6 week observational washout period without additional therapy. An additional four patients will be identified as reserve patients to be added to the cohort in case patient from the original cohort drop-out.

Based on existing biochemical data on patients attending the sub-specialty Hepatology-Diabetology NASH Clinic at St Mary's drawn from the "HEP-Base" database, 24 patients will provide 90% power to detect a 25.0 IU/l change in biochemical steatohepatitis with a significance level (alpha) of 0.05 (two-tailed). This study design offers three key benefits: (1) all patients receive the treatment, making the design efficient; (2) a control group for all patients under the same study conditions (3) all patients will be observed for a 6-12 week washout phase following Rifaximin treatment, providing data on duration of effect.

Suitable patients will be identified using the departmental HEP-Base patient database, which holds detailed clinical records for all patients seen in the sub-specialty NASH clinic at St Mary's Hospital, and assessments carried out in the Hepatology Clinical Research Facility (CRF) at St Mary's. Patients will not be randomized as they will all receive Rifaximin treatment and the same investigations. Patients will be assessed by a medical clinician at each assessment point and a dietary, drug and physical activity questionnaire will be completed and biometrics measured.

The total duration of the study is 18 months. The duration of each patient's participation is 18 weeks. Twenty four participants will be recruited directly into the study and up to 4 as reserves, all of whom will be patients with NASH.

STUDY OUTCOME MEASURES

The study outcome measures are chosen to support directly the study objectives as follows:

Primary outcome measures:

• Change in serum alanine aminotransferase (ALT) values

o by >25 IU/l (approximately 33% of mean NASH values) after 6 weeks of therapy

Secondary outcome measures:

  • Change in insulin resistance

    • assessed using the hyperinsulinaemic euglycaemic clamp method within the CRF
    • serum triglyceride levels and lipoprotein profile will also be assessed during this procedure
  • Change in hepatic triglyceride content
  • Change in serum cytokine levels
  • Change in the quantity and composition of faecal flora
  • Urinary metabolic profiling
  • Change in plasma levels of bacterial endotoxin

PARTICIPANT ENTRY

PRE-ENROLLMENT EVALUATIONS

All patients will be assessed clinically as part of their routine clinical assessment in the subspecialty NASH clinic at St Mary's Hospital. This is not considered part of the clinical study and will have occurred prior to enrolment. This assessment will include:

  • medical history
  • thorough clinical examination
  • clinical investigations to exclude coexisting liver disease, co-morbidities and medications that might confound the study outcomes, as specified in the exclusion criteria including, but not limited to:

    • serology for viral hepatitis (B, C)
    • serum iron studies
    • autoimmune screening
    • clinical serum lipid profile
    • fasting glucose and glycosylated haemoglobin
    • ultrasound of the liver

If clinically indicated, patients will have been referred for a liver biopsy for the diagnosis of suspected NASH and the resulting histology will be evaluated according to the criteria of Kleiner et al.

WITHDRAWAL CRITERIA Participants may withdraw from participation in the study at any stage, without having to give their reasons and without jeopardizing future clinical care. They will be asked their reasons for withdrawal and, if the reasons are provided, these will be included in the study data.

Other withdrawal criteria include:

  1. Any participant with a serious adverse event precluding further drug administration
  2. Significant deviation from the protocol
  3. Significant non-compliance with the study medication
  4. If the subject is no longer eligible
  5. If the subject is lost to follow-up
  6. If the Investigator believes that withdrawal is in the best interest

If participants wish to withdraw consent, data pertaining to them will be managed as follows:

  1. Participants who have not attended a study visit and not taken treatment will not be considered to have enrolled in the study and will be excluded from all analysis
  2. Participants who have attended fewer than 3 study visits and have not started the Rifaximin treatment will be excluded from all analyses
  3. Participants who have attended fewer than 3 study visits and have not completed the course of Rifaximin treatment will be included in analysis of adverse events, but excluded from analysis of the study endpoints
  4. Participants who have completed 3 or more study visits and the six-week course of Rifaximin treatment will be included in the final analysis of study endpoints

Reserve patients will be recruited in the event of participant withdrawals as per points 2 and 3 above.

Samples and data collected during the period of time that the participant has consented to the study will be retained for analysis as laid out in the study protocol.

RANDOMISATION AND ENROLLMENT PROCEDURE This is an open-label, randomized, crossover, controlled study. At the enrollment visit, a sealed envelope containing a letter assigning the participant to either group A (n=12) or group B (n=12) will be given to each participant at random by the research nurse, who will be unaware of the assignment within the envelope.

TREATMENT ARMS All participants will receive Rifaximin 400mg (as 2 x 200mg tablets) orally, twice daily for six weeks. Group A will receive Rifaximin for the first 6 weeks then SoC. Group B will receive SoC for 6 weeks then Rifaximin.

DOSE MODIFICATIONS FOR TOXICITY There are no plans for dose modifications as the drug is minimally absorbed. In addition, pre-clinical animal studies. If adverse events occur, treatment will be stopped.

INTERACTION WITH OTHER DRUGS Rifaximin does not cause cytochrome P450 enzyme induction and does not induce CYP3A4 at normal doses (in participants without severe liver dysfunction). In addition, as it is minimally absorbed, it is not considered to interact with other drugs.

ASSESSMENT AND FOLLOW-UP

The total duration of the study is 18 months. The duration of each patient's participation is 18 weeks, of which patients will only receive active treatment for 6 weeks with the remainder being SoC run-in or wash-out with SoC. Twenty four participants will be recruited initially, with up to 4 reserves, all of whom will be patients with NASH.

One screening visit will take place following liver biopsy in the sub-specialty NASH clinic at St Mary's Hospital. Enrollment and randomization will occur at the screening visit.

Following enrolment into the study, participants will attend four assessment points: baseline; six weeks; 12 weeks and 18 weeks. They will be asked to attend the NASH clinic 3 months after the end of the study for routine assessment and provision of a final urine and stool sample. At each visit study investigators will record compliance and any adverse events. Where possible, these visits will be coordinated with NASH clinic visits to minimize inconvenience to the patients.

A baseline visit will take place after the screening visit and between two weeks and one year after liver biopsy. At this visit, a clinical assessment and external examination will be made, blood will be drawn for laboratory analysis, stool provided for microbial analysis and urine provided for metabolic profiling. Investigators will assess the participant's diet and lifestyle, including the use of a brief questionnaire. All patients will undergo magnetic resonance (MR) scanning and the patients in Group A will undergo the hyperinsulinaemic euglycaemic clamp study. The patients in Group A will be given a study prescription to obtain Rifaximin from the hospital pharmacy and start the treatment for six weeks.

At six weeks, patients will attend their second assessment visit. At this visit, a clinical assessment and external examination will be made, blood will be drawn for laboratory analysis, stool provided for microbial analysis and urine provided for metabolic profiling. Investigators will assess the participant's diet and lifestyle, including the use of a brief questionnaire. All Ppatients will also undergo MR scanning and the hyperinsulinaemic euglycaemic clamp assay. The patients in Group A will have finished their course of Rifaximin and will continue SoC, while the patients in Group B will be given a study prescription to obtain Rifaximin from the hospital pharmacy and start the treatment for six weeks.

At 12 weeks, patients will attend their third assessment visit, having finished a 6 week course of Rifaximin and a 6 week course of SoC. At this visit, a clinical assessment and external examination will be made, blood will be drawn for laboratory analysis, stool provided for microbial analysis and urine provided for metabolic profiling. Investigators will assess the participant's diet and lifestyle, including the use of a brief questionnaire. All patients will undergo MR scanning and the patients in Group B will undergo the hyperinsulinaemic euglycaemic clamp study.Patients will also undergo MR scanning and the hyperinsulinaemic euglycaemic clamp assay. The patients in Group B will have finished their course of Rifaximin and all patients will continue SoC.

At 18 weeks, patients will attend their fourth and final assessment visit. At this visit, a clinical assessment and external examination will be made, blood will be drawn for laboratory analysis, stool provided for microbial analysis and urine provided for metabolic profiling. Investigators will assess the participant's diet and lifestyle, including the use of a brief questionnaire. The patients' participation in the study is now complete and they will return to the NASH clinic on a routine clinical basis as appropriate.

All participants will be invited to return to the NASH clinic 3 months after the end of their participation in the study, at which point they will undergo routine clinical assessment and, in addition, be asked to provide a stool and urine sample with a paired lifestyle questionnaire.

LOSS TO FOLLOW-UP

Given the short duration of the study, loss to follow-up is considered to be unlikely. However, If participants do not attend a scheduled visit, attempts will be made to contact them using the contact details supplied by them at their screening visit. If contact is lost, data will be included in the study analysis as follows:

  1. Participants who have not attended a study visit and not taken treatment will not be considered to have enrolled in the study and will be excluded from all analysis
  2. Participants who have attended fewer than 3 study visits and have not started the Rifaximin treatment will be excluded from all analyses
  3. Participants who have attended fewer than 3 study visits and have not completed the course of Rifaximin treatment will be included in analysis of adverse events, but excluded from analysis of the study endpoints
  4. Participants who have completed 3 or more study visits and the six-week course of Rifaximin treatment will be included in the final analysis of study endpoints

Reserve patients will be recruited in the event of participant loss to follow-up as per points 2 and 3 above.

TRIAL CLOSURE

The trial will be closed at the time that the 24th participant has completed the 18 week study period. The study will be open to recruitment until this point in case of participant withdrawal or loss to follow-up. The status of the trial will be updated on the Clinicaltrials.gov website. The clinical research unit at Imperial College London and the regional ethics committee will also be informed.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject has provided written informed consent prior to screening
  • Men and women aged 18-70 years
  • Biopsy-proven NASH with or without mild to moderate fibrosis (fibrosis stage 0-3) in the preceding year
  • Persistently abnormal ALT on 2 occasions

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01355575

Locations
United Kingdom
Liver Unit, St Mary's Hospital, Imperial College London
London, United Kingdom, W2 1NY
Sponsors and Collaborators
Imperial College London
National Health Service, United Kingdom
Investigators
Principal Investigator: Jeremy FL Cobbold, PhD Imperial College London
Study Chair: Mark R Thursz, MD Imperial College London
  More Information

No publications provided

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01355575     History of Changes
Other Study ID Numbers: 2010-021515-17, 2010-021515-17, 10/H0711/58, 45706
Study First Received: May 17, 2011
Last Updated: October 16, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Imperial College London:
Microbiota
Insulin resistance
Bacterial endotoxin
Hepatic triglyceride
Inflammation

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Digestive System Diseases
Rifaximin
Anti-Infective Agents
Gastrointestinal Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014