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

The Effect of Pentoxifylline on Nonalcoholic Steatohepatitis (NASH)

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

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Pentoxifylline; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects must be willing to give written informed consent
2. 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
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pentoxifylline; 400mg PO TID	Drug: Pentoxifylline; 400mg PO TID; Other Names: Trental
PLACEBO_COMPARATOR: Placebo; 1 pill PO TID	Drug: Placebo; 1 pill PO TID; Other Names: sugar pill

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Mary E Rinella, MD, Northwestern University

Publications and helpful links

General Publications

• Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011 Jul-Sep;10(3):277-86.

Study record dates

Study Major Dates

• Study Start: March 1, 2005
• Primary Completion (ACTUAL): September 1, 2009
• Study Completion (ACTUAL): September 1, 2009

Study Registration Dates

• First Submitted: December 12, 2005
• First Submitted That Met QC Criteria: December 20, 2005
• First Posted (ESTIMATE): December 21, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2014
• Last Update Submitted That Met QC Criteria: August 27, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Nonalcoholic Steatohepatitis; NASH; Liver; Pentoxifylline; Fatty Liver Disease; Nonalcoholic Fatty Liver Disease (NAFLD)
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: IRB # 1347-001; GCRC Protocol #891 (OTHER: Northwestern University Clinical Research Center)