Nonalcoholic Steatohepatitis
Conditions
Keywords
Fatty Liver, Nonalcoholic fatty liver disease (NALFD), NAFLD, Nonalcoholic steatohepatitis (NASH), NASH, pentoxifylline
Brief summary
One third of the population in the United States has nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, can lead to cirrhosis.Currently, there is no proven therapy for patients with NASH. The investigators core hypothesis is that therapy of patients with NASH with pentoxifylline (PTX) for one year will result in improvement of biochemical parameters of liver disease and hepatic histology. The focus of this proposal is on the effectiveness of pentoxifylline (PTX) in improving laboratory and tissue parameters of liver disease, parameters of insulin-resistance, and levels of cytokines in patients with NASH.
Interventions
400 mg PO tid
DRUGplacebo
placebo tid
Sponsors
American College of Gastroenterology
Case Western Reserve University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients ages 18 to 70 years. * Liver biopsy compatible with NASH, including presence of steatosis and necroinflammatory activity on liver biopsy done during the prior 6 months to study enrollment * Daily alcohol intake of \<30 g for males and \<15 g for females; * Appropriate exclusion of other liver diseases. * Patients with diabetes mellitus type 2 diagnosis as defined by a previous diagnosis of DM and current therapy with antidiabetic agents, or by fulfillment of 1997 American Diabetic Association (ADA) criteria, may be included if they fulfill the following criteria: (i) therapeutic regimen limited to specific oral agents including sulfonylureas (e.g. glipizide and glyburide) and/or biguanides (e.g. metformin); (ii) stable therapeutic regimen as defined by no changes in oral agents for at least 3 months; (iii) Hemoglobin A1C (HgbA1C) \< 8.5 %.
Exclusion criteria
* History of past excessive alcohol drinking (as defined above) for a period longer than 2 years at any time in the past 10 years. * Current consumption of alcohol \>30 g daily for males and \>15 g daily for females. * Positive testing for hepatitis B surface antigen, hepatitis C virus antibody, or ribonucleic acid (RNA) of hepatitis C virus of deoxyribonucleic acid (DNA) of hepatitis B virus. * Patients taking medications known to cause steatosis. * Other causes of liver disease suspected by history, family interview, or laboratory testing. * Patients with cirrhosis defined by stage 4 fibrosis on liver biopsy, or if the patient shows unequivocal clinical evidence of portal hypertension, such as thrombocytopenia, splenomegaly, or esophageal varices. * Patients taking medications of possible benefit in NASH within 3 months prior to the liver biopsy. These medications include Vitamin E, Betaine, S-adenosylmethionine (SAM-e), thiazolidinediones, and acarbose. * Patients with diabetes mellitus who are on Insulin therapy. * Patients with diabetes mellitus on therapy with thiazolidinediones or alpha-glucosidase inhibitors such as acarbose * Hypersensitivity to pentoxifylline or the methylxanthines (caffeine, theophylline, theobromine). * History of cerebral or retinal hemorrhage. * Other medical comorbidities (such as cardiac, central nervous system, renal, cancer) that would interfere with completion of the study. * Patients taking Theophylline or Coumadin because of potential drug-drug interactions with Pentoxifylline. * Pregnant or nursing women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histological Improvement of at Least 2 Points in NAFLD Activity Score (NAS) on Liver Biopsy After One Year. | 1 year (Baseline liver biopsy done at study entry, and subsequent liver biopsy done after one year of therapy with pentoxifylline or placebo) | The NAFLD Activity Score (NAS) grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and balloning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis(assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2). |
Countries
United States
Participant flow
Recruitment details
Patients were recruited between December 2006 and February 2009 at the Liver Clinics of both participating institutions.
Pre-assignment details
Patients were randomized in a double-blind fashion. Double blinding was maintained until study completion by all subjects.
Participants by arm
| Arm | Count |
|---|---|
| Pentoxifylline (PTX) 400 mg PO (by Mouth) TID 26 subjects received PTX at dose above for one year | 26 |
| Placebo TID 29 subjects received placebo as above for one year | 29 |
| Total | 55 |
Baseline characteristics
| Characteristic | Placebo TID | Pentoxifylline (PTX) 400 mg PO (by Mouth) TID | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 23 Participants | 50 Participants |
| Age Continuous | 49.6 years STANDARD_DEVIATION 9.6 | 50.5 years STANDARD_DEVIATION 12.7 | 50 years STANDARD_DEVIATION 11.1 |
| Region of Enrollment United States | 29 participants | 26 participants | 55 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 20 Participants | 18 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 26 | 14 / 29 |
| serious Total, serious adverse events | 0 / 26 | 0 / 29 |
Outcome results
Primary
Histological Improvement of at Least 2 Points in NAFLD Activity Score (NAS) on Liver Biopsy After One Year.
The NAFLD Activity Score (NAS) grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and balloning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis(assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2).
Time frame: 1 year (Baseline liver biopsy done at study entry, and subsequent liver biopsy done after one year of therapy with pentoxifylline or placebo)
Population: Intention to treat analysis included all participants and for this analysis patients without available end of study liver biopsy were imputed as treatment failures. Results showed here are continuous variable analysis of NAS score change in patients with available end of study liver biopsy (per protocol analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline 400 mg PO Tid | Histological Improvement of at Least 2 Points in NAFLD Activity Score (NAS) on Liver Biopsy After One Year. | -1.6 NAS score units | Standard Deviation 1.1 |
| Placebo Tid | Histological Improvement of at Least 2 Points in NAFLD Activity Score (NAS) on Liver Biopsy After One Year. | -0.1 NAS score units | Standard Deviation 1.4 |