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

Condition(s) targeted: Nonalcoholic Steatohepatitis; Liver Diseases

Intervention: Pentoxifylline (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Northwestern University

Official(s) and/or principal investigator(s):
Mary E Rinella, MD, Principal Investigator, Affiliation: Northwestern University

Overall contact:
Robin R Smolak, BA, Phone: 312-503-0623, Ext: 0623, Email: r-smolak@northwestern.edu

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

Official title: The Effect of Pentoxifylline on Nonalcoholic Steatohepatitis (NASH)

Study design: Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Primary outcome:

To assess the effect of pentoxifylline on serum markers of liver inflammation (ALT) in patients with NASH

To assess the effect of pentoxifylline on inflammation and fibrosis by examining liver histology in patients with NASH

Secondary outcome:

To assess the effect of pentoxifylline on cytokine levels (i.e. tumor necrosis factor [TNF]-α, interleukin-6 [IL-6], IL-10) and expression of TNF-alpha receptors (p55 and p75) in patients with NASH

To assess the effect of pentoxifylline on adipocyte-derived cytokines, leptin and adiponectin, and its effect on free fatty acid levels in patients with NASH

To assess the effect of pentoxifylline on serum markers of oxidative stress (i.e. thiobarbituric acid reactive substances [TBARS] – measure of lipid peroxidation) in patients with NASH

To determine the effect of pentoxifylline on serum markers of liver fibrosis (i.e. hyaluronic acid and procollagen III N-peptide [P-IIINP]) and correlate with liver histology

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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

Robin R Smolak, BA, Phone: 312-503-0623, Ext: 0623, Email: r-smolak@northwestern.edu

Northwestern University, Chicago, Illinois 60611, United States; Recruiting
Mary E Rinella, MD, Principal Investigator
Richard M Green, MD, Sub-Investigator
Sean WP Koppe, MD, Sub-Investigator

Starting date: March 2005
Last updated: February 9, 2006