RiFL: Rifaximin in Fatty Liver Disease

• Sponsor: Imperial College London (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01355575
• Collaborator: National Health Service, United Kingdom (Other)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 16.1
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Fatty Liver Disease; NAFLD; Nonalcoholic Steatohepatitis	Drug: Rifaximin	Phase 4

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

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• 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.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)
• Primary Purpose: Treatment
• Official Title: RiFL: Rifaximin in Fatty Liver Disease. Does Modulation of Gut Microbiota Reduce Hepatic Inflammation in Non-Alcoholic Steatohepatitis (NASH)?
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifaximin for 6-weeks followed by 6-week observation period 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.; Other Names: Xifaxan

Outcome Measures

Primary Outcome Measures

1. Serum Alanine Aminotransferase (ALT) Levels [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.

Secondary Outcome Measures

1. Insulin Resistance [Baseline and 6 weeks (end of treatment)]

   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.

2. Hepatic Triglyceride Content [Baseline and 6 weeks (end of treatment)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT01355575
• Other Study ID Numbers: 2010-021515-17; 2010-021515-17; 10/H0711/58; 45706
• First Posted: May 18, 2011
• Last Update Posted: Oct 28, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Microbiota; Insulin resistance; Bacterial endotoxin; Hepatic triglyceride; Inflammation
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Rifaximin

Study Results

Participant Flow

Arm/Group Title	Rifaximin for 6-weeks Then Standard Care
Arm/Group Description	Rifaximin for 6 weeks in addition to standard care, followed by 6 weeks observation period during which patients receive standard care. Rifaximin: Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Period Title: Overall Study
STARTED	15
COMPLETED	13
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Patients Combined
Arm/Group Description	All patients in one group
Overall Participants	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46
Sex: Female, Male (Count of Participants)
Female	2 13.3%
Male	13 86.7%

Outcome Measures

1. Primary Outcome

Title	Serum Alanine Aminotransferase (ALT) Levels
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rifaximin for 6-weeks	Standard of Care for 6-weeks
Arm/Group Description	Phase 1 Rifaximin: Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.	Phase 2 The 6-weeks Rifaximin treatment was followed by an observation period for 6-weeks during which patients received standard of care. All patients who had received Rifaximin for 6-weeks then received standard of care for the 6-week period.
Measure Participants	15	15
Median (Full Range) [iu/L]	63	83

2. Secondary Outcome

Title	Insulin Resistance
Description	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)

Outcome Measure Data

Analysis Population Description

Data not collected during standard of care.

Arm/Group Title	Rifaximin Baseline	Rifaximin After 6-weeks
Arm/Group Description	Rifaximin baseline	Rifaximin: Patients received Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Measure Participants	14	14
Median (Full Range) [% SEGP]	35.2	30

3. Secondary Outcome

Title	Hepatic Triglyceride Content
Description	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)

Outcome Measure Data

Analysis Population Description

Data not collected during standard of care.

Arm/Group Title	Rifaximin Baseline	Rifaximin After 6-weeks
Arm/Group Description	Rifaximin baseline	Rifaximin: Patients received Rifaximin tablet, oral administration, 400mg twice daily for 6 weeks.
Measure Participants	14	14
Median (Full Range) [% hepatic lipid content]	21.6	24.8

Adverse Events

Time Frame	12 weeks
Arm/Group Title	Rifaximin for 6-weeks		Standard of Care for 6-weeks
Arm/Group Description	Participants received rifaximin tablet, oral administration, 400mg twice daily for 6-weeks.		The 6-weeks Rifaximin treatment was followed by an observation period for 6-weeks during which patients received standard of care. All patients who had received Rifaximin for 6-weeks then received standard of care for the 6-week period.
All Cause Mortality
	Rifaximin for 6-weeks		Standard of Care for 6-weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Rifaximin for 6-weeks		Standard of Care for 6-weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Rifaximin for 6-weeks		Standard of Care for 6-weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		0/15 (0%)
Gastrointestinal disorders
Loose stool	1/15 (6.7%)	1	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.