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

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.

Inclusion Criteria:

1. Subjects must be willing to give written informed consent

2. Diagnosis of steatohepatitis Grade >= 1 (Brunt et al. criteria – Am J Gastroenterol
1999;94(9)2467-74) on biopsy within 6 months prior to entry into protocol

3. No histologic evidence of cirrhosis

4. Persistent ALT elevation (> 1.5 the upper limit normal) over 6 months prior to entry
into study

5. Adult subjects 18-65 years of age of any race or gender

6. 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

7. Hemoglobin A1c (HgbA1c) < 7%

8. Antinuclear antibodies (ANA) < 1:160

9. Anti-smooth muscle Ab negative

10. Serum hepatitis B surface antigen (HepBsAg) negative

11. Serum hepatitis C antibody (HepC Ab) negative

12. Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) < 45%

13. Alpha-1-antitrypsin level within normal limits

14. Ceruloplasmin level within normal limits

15. Negative pregnancy test (females)

16. Concomitant use of lipid lowering agents at study entry will not exclude patients
from the study.

Exclusion Criteria:

1. Evidence of decompensated cirrhosis

2. Active gastrointestinal (GI) bleeding

3. Renal failure (creatinine clearance < 80 mL/min)

4. Active alcohol or drug abuse

5. Uncontrolled diabetes (HgbA1c > 7)

6. Current treatment with anti-diabetic medications such as thiazolidinediones or
metformin (stable doses of sulfonylureas are acceptable)

7. Current treatment with anti-TNF alpha medication (i.e. Remicade or Enbrel)

8. Current treatment with vitamin E

9. Alcohol consumption < 20 g/day (males) or < 10 g/day (females) - assessed by one
physician and confirmed with one family member.

10. HIV positive status

11. Any history of cerebral and/or retinal hemorrhage

12. Prior intolerance of pentoxifylline or any other methylxanthine (i.e. caffeine,
theophylline, or theobromine)

13. Current use of theophylline

14. Known diagnosis of malignancy

15. Any other conditions which the investigator feels would make the subject unsuitable
for enrollment, or could interfere with the subject completing the protocol