A Phase 4 interventional study of Rifaximin in Nonalcoholic Fatty Liver Disease, NAFLD and Nonalcoholic Steatohepatitis, sponsored by Imperial College London. Terminated at 1 site in United Kingdom. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2020-10-28.
Sponsored by Imperial College London · Phase 4, Interventional, and Treatment
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:
Secondary:
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.
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.
2,081 studies on the registry are indexed under Liver Diseases; 390 are open to participants now.
This study's enrollment of 15 is below the median of 50 across 1,323 interventional studies indexed under Liver Diseases.
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Exclusion Criteria:
Other causes of chronic liver disease
Evidence of hepatic decompensation
Systemic inflammatory conditions
All patients receiving 6 weeks Rifaximin 400mg twice daily, followed by a 6 week observation period.
Drug: Rifaximin
Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Also known as: Xifaxan
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.
Time frame: Baseline, 6 weeks (end of treatment) and 12 weeks (6 weeks after end of treatment)
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.
Time frame: 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.
Time frame: Baseline and 6 weeks (end of treatment)
| Milestone | Rifaximin for 6-weeks Then Standard Care |
|---|---|
| Started | 15 |
| Completed | 13 |
| Not completed | 2 |
| Withdrew: Withdrawal by subject | 2 |
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.
| iu/L | Rifaximin for 6-weeks | Standard of Care for 6-weeks |
|---|---|---|
| Serum Alanine Aminotransferase (ALT) Levels | 63 (41 to 218) | 83 (30 to 217) |
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.
| % SEGP | Rifaximin Baseline | Rifaximin After 6-weeks |
|---|---|---|
| Insulin Resistance | 35.2 (15.3 to 51.7) | 30 (10.8 to 50.5) |
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.
| % hepatic lipid content | Rifaximin Baseline | Rifaximin After 6-weeks |
|---|---|---|
| Hepatic Triglyceride Content | 21.6 (2.2 to 46.2) | 24.8 (1.7 to 59.3) |
Collected over 12 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rifaximin for 6-weeks | 0/15 (0%) | 0/15 (0%) | 1/15 (6.7%) |
| Standard of Care for 6-weeks | 0/15 (0%) | 0/15 (0%) | 0/15 (0%) |
| Event | Rifaximin for 6-weeks | Standard of Care for 6-weeks |
|---|---|---|
| Loose stoolGastrointestinal disorders | 1/15 | 0/15 |
| Age, Continuous(years) | Patients Combined |
|---|---|
| Median | 46 (32 to 63) |
| Sex: Female, Male(Participants) | Patients Combined |
|---|---|
| Female | 2 |
| Male | 13 |
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Imperial College London