Liver Diseases, Nonalcoholic Steatohepatitis
Conditions
Keywords
Fatty Liver Disease, Liver, NASH, Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver Disease (NAFLD), Pentoxifylline
Brief summary
The purpose of this study is to explore the potential benefit of the medication, pentoxifylline, for the treatment of NASH.
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.
Interventions
DRUGPentoxifylline
400mg PO TID
DRUGPlacebo
1 pill PO TID
Sponsors
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With a 30% Reduction in Alanine Aminotransferase (ALT) Treated With Pentoxifylline (PTX) or Placebo for 12 Months. | baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Adiponectin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | one year | — |
| The Effect of Pentoxifylline on Change in Tumor Necrosis Factor [TNF]-α Levels in Patients With NASH | one year | 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. |
| Change in Serum Leptin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | baseline and one year | Values represent changes in leptin from baseline to 12 months in patients treated with pentoxifylline or placebo. |
Countries
United States
Participant flow
Recruitment details
From March 2005 to March 2008 patients were recruited through the Northwestern Memorial Faculty Foundation Hepatology Clinic.
Pre-assignment details
Subjects were excluded from the study if they had evidence of another form of liver disease or if they were HIV positive, pregnant or had evidence of ongoing alcohol consumption exceeding 20g(males) and 10g(females)daily. Furthermore, subjects were excluded if they were taking drugs known to cause steatohepatitis.
Participants by arm
| Arm | Count |
|---|---|
| Pentoxifylline Patients in this group received pentoxifylline 400mg tid for 1 year. | 19 |
| Placebo Patients in this group received a capsule identical to pentoxifylline that instead contained sucrose. | 7 |
| Total | 26 |
Baseline characteristics
| Characteristic | Placebo | Pentoxifylline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 19 Participants | 26 Participants |
| Age, Continuous | 53 years STANDARD_DEVIATION 8 | 46 years STANDARD_DEVIATION 10 | 49.5 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 7 participants | 19 participants | 26 participants |
| Sex: Female, Male Female | 3 Participants | 12 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 7 |
| serious Total, serious adverse events | 0 / 19 | 0 / 7 |
Outcome results
Primary
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.
Time frame: baseline and 12 months
Population: The primary analysis was done as intention to treat. A secondary analysis was performed per protocol and there were no differences between the two analyses. Intention to treat results are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pentoxifylline | The Number of Participants With a 30% Reduction in Alanine Aminotransferase (ALT) Treated With Pentoxifylline (PTX) or Placebo for 12 Months. | 19 participants |
| Placebo | The Number of Participants With a 30% Reduction in Alanine Aminotransferase (ALT) Treated With Pentoxifylline (PTX) or Placebo for 12 Months. | 7 participants |
Comparison: Sample size estimates were based on 30% reduction in ALT in the treatment group \& 15% reduction in the placebo group. With a sample size of 30 planned (20 treatment:10 placebo), the study was designed to have a power of 90% to detect a difference in means of 1.25 standard deviations (ES=1.25), \& a power of 80% to detect a difference in means of 1.1 standard deviations (ES=1.1), based on calculations using power index, z-table, \& accounting for unequal sample size: n1 = 20, n2 = 10, a = 0.05.p-value: 0.46ANOVA
Secondary
Change in Serum Adiponectin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months
Time frame: one year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline | Change in Serum Adiponectin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | 0.4 ug/mL | Standard Error 0.3 |
| Placebo | Change in Serum Adiponectin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | 0.8 ug/mL | Standard Error 0.4 |
p-value: 0.49t-test, 2 sided
Secondary
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.
Time frame: baseline and one year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline | Change in Serum Leptin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | 0.78 ng/mL | Standard Error 0.07 |
| Placebo | Change in Serum Leptin Levels in Patients Treated With Pentoxifylline or Placebo for 12 Months | 0.78 ng/mL | Standard Error 0.08 |
p-value: 0.94t-test, 2 sided
Secondary
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.
Time frame: one year
Population: Intention to Treat with last observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentoxifylline | The Effect of Pentoxifylline on Change in Tumor Necrosis Factor [TNF]-α Levels in Patients With NASH | -117.9 pg/dL | Standard Error 109.5 |
| Placebo | The Effect of Pentoxifylline on Change in Tumor Necrosis Factor [TNF]-α Levels in Patients With NASH | 18.3 pg/dL | Standard Error 64.4 |
Comparison: Null hypothesis was that there was no difference between mean hepatic expression of TNF-alpha receptors in patient with NASH. This was a secondary outcome and no power analysis was done.p-value: 0.16t-test, 2 sided