Pentoxifylline/Nonalcoholic Steatohepatitis (NASH) Study: The Effect of Pentoxifylline on NASH

Study Overview
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Brief Summary
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The purpose of this study is to explore the potential benefit of the medication, pentoxifylline, for the treatment of NASH.

Detailed Description
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This is an investigational study looking at subjects who have been diagnosed with nonalcoholic steatohepatitis (NASH) or 'fatty liver disease'. There is currently no FDA approved available treatment for NASH. The purpose of this study is to explore the potential benefit of the medication, pentoxifylline, for the treatment of NASH. The effectiveness of this drug will be determined by taking blood samples and a liver biopsy. To determine if there is any effect of the medication, two-thirds of the patients participating in the study will receive pentoxifylline and one-third will receive placebo (sugar pill). Thus, an individual's chance of receiving the drug is 67%. In addition to receiving a study drug (placebo or pentoxifylline) the subjects will be encouraged to achieve modest weight loss ( 1-2 lbs/week) via low-fat diet and exercise. The drug (Pentoxifylline) being studied is not approved for use in people who have NASH. Pentoxifylline is considered experimental in this study. Pentoxifylline has been safely used for the treatment of other medical conditions such as alcohol related liver disease and poor circulation. Pentoxifylline is a pill which is taken three times a day.

Official Title
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The Effect of Pentoxifylline on Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis, Liver Diseases

Intervention / Treatment
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* Drug: Pentoxifylline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be willing to give written informed consent Diagnosis of steatohepatitis Grade >= 1 (Brunt et al. criteria - Am J Gastroenterology 1999;94(9)2467-74) on biopsy within 6 months prior to entry into protocol No histologic evidence of cirrhosis Persistent ALT elevation (> 1.5 the upper limit normal) over 6 months prior to entry into study Adult subjects 18-65 years of age of any race or gender Compensated liver disease with the following hematologic, biochemical, and serological criteria on entry into protocol: Hemoglobin > 11 gm/dL for females and > 12 gm/dL for males White blood cell (WBC) > 2.5 K/UL Neutrophil count > 1.5 K/UL Platelets > 100 K/UL Direct bilirubin, within normal limits Indirect bilirubin within normal limits (unless non-hepatitis factors such as Gilbert's disease explain indirect bilirubin rise. In such cases total bilirubin must be < 3.0 mg/dL) Albumin > 3.2 g/dL Serum creatinine within normal limits Hemoglobin A1c (HgbA1c) < 7% Antinuclear antibodies (ANA) < 1:160 Anti-smooth muscle Ab negative Serum hepatitis B surface antigen (HepBsAg) negative Serum hepatitis C antibody (HepC Ab) negative Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) < 45% Alpha-1-antitrypsin level within normal limits Ceruloplasmin level within normal limits Negative pregnancy test (females) Concomitant use of lipid lowering agents at study entry will not exclude patients from the study. Exclusion Criteria: Evidence of decompensated cirrhosis Active gastrointestinal (GI) bleeding Renal failure (creatinine clearance < 80 mL/min) Active alcohol or drug abuse Uncontrolled diabetes (HgbA1c > 7) Current treatment with anti-diabetic medications such as thiazolidinediones or metformin (stable doses of sulfonylureas are acceptable) Current treatment with anti-TNF alpha medication (i.e. Remicade or Enbrel) Current treatment with vitamin E Alcohol consumption < 20 g/day (males) or < 10 g/day (females) - assessed by one physician and confirmed with one family member. HIV positive status Any history of cerebral and/or retinal hemorrhage Prior intolerance of pentoxifylline or any other methylxanthine (i.e. caffeine, theophylline, or theobromine) Current use of theophylline Known diagnosis of malignancy Any other conditions which the investigator feels would make the subject unsuitable for enrollment, or could interfere with the subject completing the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxifylline<br>400mg PO TID | Drug: Pentoxifylline<br>* 400mg PO TID<br>* Other names: Trental;|
| Placebo Comparator: Placebo<br>1 pill PO TID | Drug: Placebo<br>* 1 pill PO TID<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With a 30% Reduction in Alanine Aminotransferase (ALT) Treated With Pentoxifylline (PTX) or Placebo for 12 Months. | The primary goal of the study was to determine whether pentoxifylline (PTX) therapy improved serum ALT (> or = 30% change from baseline to month 12) compared to placebo. | baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Pentoxifylline on Change in Tumor Necrosis Factor [TNF]-α Levels in Patients With NASH | The mean change from baseline to month 12 in proinflammatory cytokines (such as TNF-α) and gene expresssion were the secondary endpoints and were analyzed with the same analysis of covariance model and summary statistics specified for the primary endpoint. Differences were regarded as statistically significant when P < 0.05. The results for TNF-α are reported here. Interleukin-6 [IL-6], IL-10) and expression of TNF-alpha Receptors (p55 and p75) had insufficient data for statistical analysis. | one year | 
| Change in Serum Leptin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | Values represent changes in leptin from baseline to 12 months in patients treated with pentoxifylline or placebo. | baseline and one year | 
| Change in Serum Adiponectin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months |  | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fatty Liver Disease, Liver, NASH, Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver Disease (NAFLD), Pentoxifylline