Nonalcoholic Fatty Liver DiseasePhase 4RiFLNCT01355575
Rifaximin in Fatty Liver Disease
A Phase 4 study testing Rifaximin in people with Nonalcoholic Fatty Liver Disease and NAFLD, run by Imperial College London at 1 site in United Kingdom.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Nonalcoholic Fatty Liver Disease, NAFLD, Nonalcoholic Steatohepatitis
- What is being tested?
- Rifaximin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- May 2011to Sep 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 28Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Liver Unit, St Mary's Hospital, Imperial College London
London, W2 1NY
About this study
Official title: RiFL: Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?
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
Read more
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.
Read the 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.
- Being tested
- Rifaximin
- Keywords
- Microbiota, Insulin resistance, Bacterial endotoxin, Hepatic triglyceride, Inflammation
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Insulin Resistance, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RifaximinDrug
Also called Xifaxan
Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Rifaximin for 6-weeks followed by 6-week observation period | Experimental | All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period. Receives: Drug: Rifaximin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment)
Secondary outcomes (2)
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.
Measured: 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.
Measured: Baseline and 6 weeks (end of treatment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 May 2011 (estimated)
- Study startMay 2011
- Primary completionSep 2012
- Study completionSep 2012
Why it stopped: Primary endpoint data review concluded no further patients required.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Nonalcoholic Fatty Liver DiseaseStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- National Health Service, United Kingdom
- Responsible party
- Sponsor
- Investigators
- Jeremy FL Cobbold, PhD, Principal investigator, Imperial College LondonMark R Thursz, MD, Study chair, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01355575
- Sponsor's protocol ID
- 2010-021515-17
- Other IDs
- 2010-021515-17, 10/H0711/58, 45706
- Acronym
- RiFL
- Status last verified
- Oct 2020
- First submitted
- 17 May 2011
- Last updated
- 28 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RiFL: Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?
- ClinicalTrials.gov ID
- NCT01355575
- Acronym / sponsor ID
- RiFL / 2010-021515-17
- Keywords
- Microbiota, Insulin resistance, Bacterial endotoxin, Hepatic triglyceride, Inflammation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Primary endpoint data review concluded no further patients required.
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- National Health Service, United Kingdom
- Study start
- May 2011
- Primary completion
- Sep 2012 (actual)
- Study completion
- Sep 2012 (actual)
- First posted
- 18 May 2011 (estimated)
- Results
- Posted 4 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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.
| Arm | Type | Receives |
|---|---|---|
| Rifaximin for 6-weeks followed by 6-week observation period | Experimental | Drug: RifaximinAll patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (28 listed)
- NAFLD with cirrhosis (fibrosis score 4)
- Other causes of chronic liver disease
- Evidence of hepatic decompensation
- Moderate or severe renal dysfunction (CKD3+, estimated GFR <60ml/min/1.73m2)
- Hepatocellular carcinoma
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RifaximinAlso: XifaxanRifaximin tablet, oral administration, 400mg twice daily for 6 weeks. | Drug | Rifaximin for 6-weeks followed by 6-week observation period |
Primary outcome
Serum Alanine Aminotransferase (ALT) Levels
Time frame: Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment)
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.
2 secondary outcomes
Insulin Resistance
Time frame: Baseline and 6 weeks (end of treatment)
Hepatic Triglyceride Content
Time frame: Baseline and 6 weeks (end of treatment)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeremy FL Cobbold, PhD principal investigator
Imperial College London
Mark R Thursz, MD study chair
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Rifaximin in people with Nonalcoholic Fatty Liver Disease and NAFLD, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Alanine Aminotransferase (ALT) Levels (time frame: Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2020.